U.S. patent application number 14/960707 was filed with the patent office on 2016-08-04 for genetic polymorphisms associated with autoinflammatory diseases, methods of detection and uses thereof.
The applicant listed for this patent is CELERA CORPORATION. Invention is credited to Yonghong LI, Steven SCHRODI.
Application Number | 20160222450 14/960707 |
Document ID | / |
Family ID | 41466299 |
Filed Date | 2016-08-04 |
United States Patent
Application |
20160222450 |
Kind Code |
A1 |
SCHRODI; Steven ; et
al. |
August 4, 2016 |
GENETIC POLYMORPHISMS ASSOCIATED WITH AUTOINFLAMMATORY DISEASES,
METHODS OF DETECTION AND USES THEREOF
Abstract
The present invention provides compositions and methods based on
genetic polymorphisms that are associated with autoinflammatory
diseases such as psoriasis. For example, the present invention
relates to nucleic acid molecules containing the polymorphisms,
variant proteins encoded by these nucleic acid molecules, reagents
for detecting the polymorphic nucleic acid molecules and variant
proteins, and methods of using the nucleic acid molecules and
proteins as well as methods of using reagents for their
detection.
Inventors: |
SCHRODI; Steven;
(Marshfield, WI) ; LI; Yonghong; (Palo Alto,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CELERA CORPORATION |
Alameda |
CA |
US |
|
|
Family ID: |
41466299 |
Appl. No.: |
14/960707 |
Filed: |
December 7, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13855547 |
Apr 2, 2013 |
|
|
|
14960707 |
|
|
|
|
12494800 |
Jun 30, 2009 |
|
|
|
13855547 |
|
|
|
|
61134042 |
Jul 2, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12Q 2600/136 20130101;
C12Q 2600/172 20130101; A61P 37/06 20180101; C12Q 1/6883 20130101;
C12Q 2600/156 20130101; C12Q 2600/106 20130101; C12Q 2600/158
20130101; C07K 16/244 20130101 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; C07K 16/24 20060101 C07K016/24 |
Claims
1. A method of determining whether a human has an altered risk for
autoinflammatory disease, comprising testing nucleic acid from said
human for the presence or absence of a polymorphism selected from
the group consisting of the polymorphisms as represented by
position 101 of any one of the nucleotide sequences of SEQ ID
NOS:219, 21-218, and 220-307 or its complement, wherein said
polymorphism indicates said human has an altered risk for
autoinflammatory disease.
2. The method of claim 1, wherein said autoinflammatory disease is
psoriasis or Crohn's disease.
3. The method of claim 1, wherein said altered risk is an increased
risk.
4. The method of claim 1, wherein said altered risk is a decreased
risk.
5-7. (canceled)
8. The method of claim 1, wherein said nucleic acid is a nucleic
acid extract from a biological sample from said human.
9. The method of claim 8, wherein said biological sample is blood,
saliva, or buccal cells.
10. The method of claim 8, further comprising preparing said
nucleic acid extract from said biological sample prior to said
testing step.
11. The method of claim 10, further comprising obtaining said
biological sample from said human prior to said preparing step.
12. The method of claim 1, wherein said testing step comprises
nucleic acid amplification.
13. The method of claim 12, wherein said nucleic acid amplification
is carried out by polymerase chain reaction.
14. The method of claim 1, further comprising correlating the
presence or absence of said polymorphism with an altered risk for
autoinflammatory disease.
15. The method of claim 14, wherein said correlating step is
performed by computer software.
16. The method of claim 1, wherein said testing is performed using
sequencing, 5' nuclease digestion, molecular beacon assay,
oligonucleotide ligation assay, size analysis, single-stranded
conformation polymorphism analysis, or denaturing gradient gel
electrophoresis (DGGE).
17. The method of claim 1, wherein said testing is performed using
an allele-specific method.
18. The method of claim 17, wherein said allele-specific method is
allele-specific probe hybridization, allele-specific primer
extension, or allele-specific amplification.
19. The method of claim 18, wherein said method is performed using
an allele-specific primer provided in Table 3.
20. The method of claim 1 which is an automated method.
21. The method of claim 1, further comprising correlating the
presence of said polymorphism with said human's responsiveness to a
therapeutic agent.
22. The method of claim 21, wherein said therapeutic agent
comprises an anti-IL12 or anti-IL23 antibody.
23-25. (canceled)
26. A method for reducing risk of autoinflammatory disease in a
human, comprising administering to said human an effective amount
of a therapeutic agent, said human having been identified as having
an increased risk for autoinflammatory disease due to the presence
or absence of a polymorphism selected from the group consisting of
the polymorphisms as represented by position 101 of any one of the
nucleotide sequences of SEQ ID NOS:219, 21-218, and 220-307 or its
complement.
27. The method of claim 26, wherein said method comprises testing
nucleic acid from said human for the presence or absence of said
polymorphism.
28. The method of claim 26, wherein said autoinflammatory disease
is psoriasis or Crohn's disease.
29. (canceled)
30. The method of claim 26, wherein said therapeutic agent targets
at least one of IL12 and IL23.
31. The method of claim 30, wherein said therapeutic agent
comprises an anti-IL12 or anti-IL23 antibody.
32. The method of claim 31, wherein said therapeutic agent
comprises an anti-IL-12p40 antibody selected from the group
consisting of ABT-874 and CNTO-1275.
33-38. (canceled)
39. A kit for determining whether a human has an altered risk for
autoinflammatory disease, wherein said kit comprises at least one
container and at least one oligonucleotide stored in said
container, wherein said oligonucleotide is capable of detecting the
presence or absence of a polymorphism selected from the group
consisting of the polymorphisms as represented by position 101 of
any one of the nucleotide sequences of SEQ ID NOS:219, 21-218, and
220-307 or its complement.
40. The kit of claim 39, wherein said oligonucleotide selectively
hybridizes to said nucleic acid in the presence of said
polymorphism and does not hybridize to said nucleic acid in the
absence of said polymorphism.
41. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
non-provisional application Ser. No. 13/855,547, filed Apr. 2,
2013, which is a continuation application of U.S. non-provisional
application Ser. No. 12/494,800, filed Jun. 30, 2009, which is a
non-provisional application of U.S. provisional application Ser.
No. 61/134,042, filed Jul. 2, 2008, the contents of each of which
are hereby incorporated by reference in their entirety into this
application.
FIELD OF THE INVENTION
[0002] The present invention is in the field of diagnosis and
therapy of autoinflammatory diseases, as well as drug response. In
particular, the present invention relates to specific single
nucleotide polymorphisms (SNPs) in the human genome, and their
association with psoriasis and related pathologies. The SNPs
disclosed herein can be used as targets for the design of
diagnostic reagents and the development of therapeutic agents, as
well as for disease association and linkage analysis. In
particular, the SNPs of the present invention are useful for such
uses as identifying an individual who has an increased or decreased
risk of developing psoriasis, for early detection of the disease,
for providing clinically important information for the prevention
and/or treatment of psoriasis, for predicting progression or
recurrence of psoriasis, for predicting the seriousness or
consequences of psoriasis in an individual, for determining the
prognosis of an individual's recovery from psoriasis, for screening
and selecting therapeutic agents, and for predicting a patient's
response to therapeutic agents (such as evaluating the likelihood
of an individual responding positively to a particular therapeutic
agent), particularly for the treatment or prevention of psoriasis.
The SNPs disclosed herein are also useful for human identification
applications. Methods, assays, kits, and reagents for detecting the
presence of these polymorphisms and their encoded products are
provided.
BACKGROUND OF THE INVENTION
[0003] Examples of autoinflammatory diseases include inflammatory
and autoimmune disorders such as psoriasis, inflammatory bowel
disease (IBD) (including Crohn's disease, which further includes
both adult and pediatric Crohn's disease, and ulcerative colitis)
and other chronic inflammatory disorders, atopic dermatitis,
multiple sclerosis, rheumatoid arthritis (RA), ankylosing
spondylitis (AS), celiac disease, Graves' disease (including
Graves' ophthalmopathy (GO) and Graves' disease without
opthalmopathy), and Barrett's esophagus.
[0004] Psoriasis is described here as an example of an
autoinflammatory disease.
[0005] Psoriasis
[0006] Psoriasis is a common, chronic, T-cell-mediated inflammatory
disease of the skin affecting .about.2-3% of whites of European
descent. Although this disease is found in all populations, its
prevalence is lower in Asians and African-Americans and also
declines at lower latitudes. The most common form, psoriasis
vulgaris, is characterized by varying numbers of red, raised, scaly
skin patches that can be present on any body surface, but most
often appear on the elbows, knees and scalp. The onset of disease
usually occurs early in life (15-30 years) and affects males and
females equally. Up to 30% of individuals with psoriasis will
develop an inflammatory arthritis, which can affect the peripheral
joints of the hands and feet, large joints, or the central
axial-skeleton. Pathologically, psoriasis is characterized by
vascular changes, hyperproliferation of keratinocytes, altered
epidermal differentiation and inflammation. In particular, the
reaction of cells in the epidermis to type 1 effector molecules
produced by T-cells results in the characteristic pathology of the
plaques.
[0007] The genetics of psoriasis are complex and highly heritable
as evidenced by an increased rate of concordance in monozygotic
twins over dizygotic twins (35%-72% vs. 12-23%) and a substantially
increased incidence in family members of affected individuals
(first-degree relatives 6%); however, it is clear that
environmental effects are also responsible for disease
susceptibility. Ten genome-wide linkage scans have resulted in
strong evidence for a susceptibility locus in the MHC region on
6p21 (PSORS1 [MIM 177900]), but have not yielded consistent
evidence for other regions.
[0008] Linkage and association in the MHC (6p21) are thought to be
due to HLA-C, in particular psoriasis susceptibility effects are
thought to be caused by the *0602 allele, although other candidate
genes in the area may also contribute to disease predisposition.
Association studies have identified three genes under linkage
peaks, with considerable evidence for linkage disequilibrium with
psoriasis, namely SLC9A3R1/NAT9 and RAPTOR (KIAA1303) in 17q25, and
SLC12A8 in 3q21. Several other genes including VDR, MMP2, IL10,
IL1RN, IL12B, and IRF2 (Genetic Association Database, OMIM) have
been associated with psoriasis in sample sets of varying sizes and
of different ethnicities; however, without more data from
additional independent studies, it is difficult to draw
statistically sound conclusions about whether these markers are
truly associated with disease. Thus, there remains a need for the
discovery of reliable markers that can associate themselves with
psoriasis, and in turn, would facilitate the diagnosis and
treatment of the disease.
[0009] The discovery of genetic markers which are useful in
identifying psoriasis individuals who are at increased risk for
developing psoriasis may lead to, for example, better therapeutic
strategies, economic models, and health care policy decisions.
[0010] Single Nucleotide Polymorphisms (SNPs)
[0011] The genomes of all organisms undergo spontaneous mutation in
the course of their continuing evolution, generating variant forms
of progenitor genetic sequences. Gusella, Ann Rev Biochem
55:831-854 (1986). A variant form may confer an evolutionary
advantage or disadvantage relative to a progenitor form or may be
neutral. In some instances, a variant form confers an evolutionary
advantage to the species and is eventually incorporated into the
DNA of many or most members of the species and effectively becomes
the progenitor form. Additionally, the effects of a variant form
may be both beneficial and detrimental, depending on the
circumstances. For example, a heterozygous sickle cell mutation
confers resistance to malaria, but a homozygous sickle cell
mutation is usually lethal. In many cases, both progenitor and
variant forms survive and co-exist in a species population. The
coexistence of multiple forms of a genetic sequence gives rise to
genetic polymorphisms, including SNPs.
[0012] Approximately 90% of all genetic polymorphisms in the human
genome are SNPs. SNPs are single base positions in DNA at which
different alleles, or alternative nucleotides, exist in a
population. The SNP position (interchangeably referred to herein as
SNP, SNP site, SNP locus, SNP marker, or marker) is usually
preceded by and followed by highly conserved sequences of the
allele (e.g., sequences that vary in less than 1/100 or 1/1000
members of the populations). An individual may be homozygous or
heterozygous for an allele at each SNP position. A SNP can, in some
instances, be referred to as a "cSNP" to denote that the nucleotide
sequence containing the SNP is an amino acid coding sequence.
[0013] A SNP may arise from a substitution of one nucleotide for
another at the polymorphic site. Substitutions can be transitions
or transversions. A transition is the replacement of one purine
nucleotide by another purine nucleotide, or one pyrimidine by
another pyrimidine. A transversion is the replacement of a purine
by a pyrimidine, or vice versa. A SNP may also be a single base
insertion or deletion variant referred to as an "indel." Weber et
al., "Human diallelic insertion/deletion polymorphisms," Am J Hum
Genet 71(4):854-62 (October 2002).
[0014] A synonymous codon change, or silent mutation/SNP (terms
such as "SNP," "polymorphism," "mutation," "mutant," "variation,"
and "variant" are used herein interchangeably), is one that does
not result in a change of amino acid due to the degeneracy of the
genetic code. A substitution that changes a codon coding for one
amino acid to a codon coding for a different amino acid (i.e., a
non-synonymous codon change) is referred to as a missense mutation.
A nonsense mutation results in a type of non-synonymous codon
change in which a stop codon is formed, thereby leading to
premature termination of a polypeptide chain and a truncated
protein. A read-through mutation is another type of non-synonymous
codon change that causes the destruction of a stop codon, thereby
resulting in an extended polypeptide product. While SNPs can be
bi-, tri-, or tetra-allelic, the vast majority of the SNPs are
bi-allelic, and are thus often referred to as "bi-allelic markers,"
or "di-allelic markers."
[0015] As used herein, references to SNPs and SNP genotypes include
individual SNPs and/or haplotypes, which are groups of SNPs that
are generally inherited together. Haplotypes can have stronger
correlations with diseases or other phenotypic effects compared
with individual SNPs, and therefore may provide increased
diagnostic accuracy in some cases. Stephens et al., Science
293:489-493 (July 2001).
[0016] Causative SNPs are those SNPs that produce alterations in
gene expression or in the expression, structure, and/or function of
a gene product, and therefore are most predictive of a possible
clinical phenotype. One such class includes SNPs falling within
regions of genes encoding a polypeptide product, i.e. cSNPs. These
SNPs may result in an alteration of the amino acid sequence of the
polypeptide product (i.e., non-synonymous codon changes) and give
rise to the expression of a defective or other variant protein.
Furthermore, in the case of nonsense mutations, a SNP may lead to
premature termination of a polypeptide product. Such variant
products can result in a pathological condition, e.g., genetic
disease. Examples of genes in which a SNP within a coding sequence
causes a genetic disease include sickle cell anemia and cystic
fibrosis.
[0017] Causative SNPs do not necessarily have to occur in coding
regions; causative SNPs can occur in, for example, any genetic
region that can ultimately affect the expression, structure, and/or
activity of the protein encoded by a nucleic acid. Such genetic
regions include, for example, those involved in transcription, such
as SNPs in transcription factor binding domains, SNPs in promoter
regions, in areas involved in transcript processing, such as SNPs
at intron-exon boundaries that may cause defective splicing, or
SNPs in mRNA processing signal sequences such as polyadenylation
signal regions. Some SNPs that are not causative SNPs nevertheless
are in close association with, and therefore segregate with, a
disease-causing sequence. In this situation, the presence of a SNP
correlates with the presence of, or predisposition to, or an
increased risk in developing the disease. These SNPs, although not
causative, are nonetheless also useful for diagnostics, disease
predisposition screening, and other uses.
[0018] An association study of a SNP and a specific disorder
involves determining the presence or frequency of the SNP allele in
biological samples from individuals with the disorder of interest,
such as psoriasis, and comparing the information to that of
controls (i.e., individuals who do not have the disorder; controls
may be also referred to as "healthy" or "normal" individuals) who
are preferably of similar age and race. The appropriate selection
of patients and controls is important to the success of SNP
association studies. Therefore, a pool of individuals with
well-characterized phenotypes is extremely desirable.
[0019] A SNP may be screened in diseased tissue samples or any
biological sample obtained from a diseased individual, and compared
to control samples, and selected for its increased (or decreased)
occurrence in a specific pathological condition, such as
pathologies related to psoriasis. Once a statistically significant
association is established between one or more SNP(s) and a
pathological condition (or other phenotype) of interest, then the
region around the SNP can optionally be thoroughly screened to
identify the causative genetic locus/sequence(s) (e.g., causative
SNP/mutation, gene, regulatory region, etc.) that influences the
pathological condition or phenotype. Association studies may be
conducted within the general population and are not limited to
studies performed on related individuals in affected families
(linkage studies).
[0020] Clinical trials have shown that patient response to
treatment with pharmaceuticals is often heterogeneous. There is a
continuing need to improve pharmaceutical agent design and therapy.
In that regard, SNPs can be used to identify patients most suited
to therapy with particular pharmaceutical agents (this is often
termed "pharmacogenomics"). Similarly, SNPs can be used to exclude
patients from certain treatment due to the patient's increased
likelihood of developing toxic side effects or their likelihood of
not responding to the treatment. Pharmacogenomics can also be used
in pharmaceutical research to assist the drug development and
selection process. Linder et al., Clinical Chemistry 43:254 (1997);
Marshall, Nature Biotechnology 15:1249 (1997); International Patent
Application WO 97/40462, Spectra Biomedical; and Schafer et al.,
Nature Biotechnology 16:3 (1998).
SUMMARY OF THE INVENTION
[0021] The present invention relates to the identification of SNPs,
as well as unique combinations of such SNPs and haplotypes of SNPs,
that are associated with autoinflammatory diseases such as
psoriasis, particularly an increased or decreased risk of
developing autoinflammatory diseases and responsiveness to
therapies used to treat autoinflammatory diseases. The
polymorphisms disclosed herein are directly useful as targets for
the design of diagnostic and prognostic reagents and the
development of therapeutic and preventive agents for use in the
diagnosis, prognosis, treatment, and/or prevention of psoriasis, as
well as for predicting a patient's response to therapeutic agents,
particularly for the treatment or prevention of psoriasis.
[0022] Based on the identification of SNPs associated with
psoriasis, the present invention also provides methods of detecting
these variants as well as the design and preparation of detection
reagents needed to accomplish this task. The invention specifically
provides, for example, SNPs associated with psoriasis, isolated
nucleic acid molecules (including DNA and RNA molecules) containing
these SNPs, variant proteins encoded by nucleic acid molecules
containing such SNPs, antibodies to the encoded variant proteins,
computer-based and data storage systems containing the novel SNP
information, methods of detecting these SNPs in a test sample,
methods of identifying individuals who have an altered (i.e.,
increased or decreased) risk of developing psoriasis, methods for
determining the risk of an individual for recurring psoriasis,
methods for prognosing the severity or consequences of psoriasis,
methods of treating an individual who has an increased risk for
psoriasis, and methods for identifying individuals (e.g.,
determining a particular individual's likelihood) who have an
altered (i.e., increased or decreased) likelihood of responding to
a drug treatment, particularly drug treatment of psoriasis, based
on the presence or absence of one or more particular nucleotides
(alleles) at one or more SNP sites disclosed herein or the
detection of one or more encoded variant products (e.g., variant
mRNA transcripts or variant proteins), methods of identifying
individuals who are more or less likely to respond to a treatment
(or more or less likely to experience undesirable side effects from
a treatment), methods of screening for compounds useful in the
treatment or prevention of a disorder associated with a variant
gene/protein, compounds identified by these methods, methods of
treating or preventing disorders mediated by a variant
gene/protein, methods of using the novel SNPs of the present
invention for human identification, etc.
[0023] The present invention further provides methods for selecting
or formulating a treatment regimen (e.g., methods for determining
whether or not to administer a drug treatment to an individual
having psoriasis, or who is at risk for developing psoriasis in the
future, or who has previously had psoriasis, methods for selecting
a particular treatment regimen such as dosage and frequency of
administration of a drug, or a particular form/type of a drug such
as a particular pharmaceutical formulation or compound, methods for
administering an alternative treatment to individuals who are
predicted to be unlikely to respond positively to a particular
treatment, etc.), and methods for determining the likelihood of
experiencing toxicity or other undesirable side effects from a drug
treatment, etc. The present invention also provides methods for
selecting individuals to whom a therapeutic agent will be
administered based on the individual's genotype, and methods for
selecting individuals for a clinical trial of a therapeutic agent
based on the genotypes of the individuals (e.g., selecting
individuals to participate in the trial who are most likely to
respond positively from a drug treatment and/or excluding
individuals from the trial who are unlikely to respond positively
from a drug treatment based on their SNP genotype(s), or selecting
individuals who are unlikely to respond positively to a particular
drug treatment based on their SNP genotype(s) to participate in a
clinical trial of another type of drug that may benefit them). The
present invention further provides methods for reducing an
individual's risk of developing psoriasis using a drug treatment,
including preventing recurring psoriasis using a drug treatment,
when said individual carries one or more SNP alleles identified
herein as being associated with psoriasis.
[0024] In Tables 1 and 2, the present invention provides gene
information, references to the identification of transcript
sequences (SEQ ID NOS:1-2), encoded amino acid sequences (SEQ ID
NOS:3-4), genomic sequences (SEQ ID NOS:13-20), transcript-based
context sequences (SEQ ID NOS:5-12) and genomic-based context
sequences (SEQ ID NOS:21-307) that contain the SNPs of the present
invention, and extensive SNP information that includes observed
alleles, allele frequencies, populations/ethnic groups in which
alleles have been observed, information about the type of SNP and
corresponding functional effect, and, for cSNPs, information about
the encoded polypeptide product. The actual transcript sequences
(SEQ ID NOS:1-2), amino acid sequences (SEQ ID NOS:3-4), genomic
sequences (SEQ ID NOS:13-20), transcript-based SNP context
sequences (SEQ ID NOS:5-12), and genomic-based SNP context
sequences (SEQ ID NOS:21-307), together with primer sequences (SEQ
ID NOS:308-541) are provided in the Sequence Listing.
[0025] In certain exemplary embodiments, the invention provides
methods for identifying an individual who has an altered risk for
developing psoriasis (including, for example, a first incidence
and/or a recurrence of the disease), in which the method comprises
detecting a single nucleotide polymorphism (SNP) in any one of the
nucleotide sequences of SEQ ID NOS:1-2, SEQ ID NOS:5-12, SEQ ID
NOS:13-20, and SEQ ID NOS:21-307 in said individual's nucleic
acids, wherein the SNP is specified in Table 1 and/or Table 2, and
the presence of the SNP is indicative of an altered risk for
psoriasis in said individual. In certain exemplary embodiments of
the invention, SNPs that occur naturally in the human genome are
provided as isolated nucleic acid molecules. These SNPs are
associated with psoriasis such that they can have a variety of uses
in the diagnosis, prognosis, treatment, and/or prevention of
psoriasis and related pathologies (e.g., Crohn's disease and other
autoinflammatory diseases). In an alternative embodiment, a nucleic
acid of the invention is an amplified polynucleotide, which is
produced by amplification of a SNP-containing nucleic acid
template. In another embodiment, the invention provides for a
variant protein that is encoded by a nucleic acid molecule
containing a SNP disclosed herein.
[0026] In yet another embodiment of the invention, a reagent for
detecting a SNP in the context of its naturally-occurring flanking
nucleotide sequences (which can be, e.g., either DNA or mRNA) is
provided. In particular, such a reagent may be in the form of, for
example, a hybridization probe or an amplification primer that is
useful in the specific detection of a SNP of interest. In an
alternative embodiment, a protein detection reagent is used to
detect a variant protein that is encoded by a nucleic acid molecule
containing a SNP disclosed herein. A preferred embodiment of a
protein detection reagent is an antibody or an antigen-reactive
antibody fragment.
[0027] Various embodiments of the invention also provide kits
comprising SNP detection reagents, and methods for detecting the
SNPs disclosed herein by employing detection reagents. In a
specific embodiment, the present invention provides for a method of
identifying an individual having an increased or decreased risk of
developing psoriasis by detecting the presence or absence of one or
more SNP alleles disclosed herein. In another embodiment, a method
for diagnosis of psoriasis by detecting the presence or absence of
one or more SNP alleles disclosed herein is provided. The present
invention also provides methods for evaluating whether an
individual is likely (or unlikely) to respond to a drug treatment,
particularly treatment of psoriasis, by detecting the presence or
absence of one or more SNP alleles disclosed herein.
[0028] For example, the SNP allele can be an allele of an IL12B
region SNP selected from the group consisting of rs2546892,
rs1433048, rs6894567, rs17860508, rs7709212, rs953861, rs6869411,
rs1833754, rs6861600, rs1368437, rs2082412, rs7730390, rs3181225,
rs1368439, rs3212227, rs3213120, rs3213119, and rs2853696 (see
Tables 9-10), and the SNPs provided in Table 11 (e.g., rs1422878),
or a combination of any number of these. Exemplary combinations
include combinations consisting of, consisting essentially of, and
comprising the nine IL12B region SNPs rs2546892, rs1433048,
rs6894567, rs17860508, rs7709212, rs953861, rs6869411, rs1833754,
and rs6861600 (see Table 9) and combinations consisting of,
consisting essentially of, and comprising the nine IL12B region
SNPs rs1368437, rs2082412, rs7730390, rs3181225, rs1368439,
rs3212227, rs3213120, rs3213119, and rs2853696 (see Table 10).
These and other combinations can further include one or more SNPs
provided in Table 11 (e.g., rs1422878).
[0029] Further, the SNP allele can be an allele of an IL23R region
SNP selected from the group consisting of rs7530511, rs10489629,
rs4655692, rs2201841, rs11465804, rs10489628, rs1343152,
rs10789229, rs10889671, rs11209026, rs10889674, rs12085634,
rs1343151, rs1008193, rs6693831, rs10889675, rs11465827,
rs10889677, rs4655531, rs11209030, rs1857292, rs11209031, and
rs11209032 (see Table 7), including combinations consisting of,
consisting essentially of, and comprising any of these 23 SNPs.
Exemplary combinations include combinations consisting of,
consisting essentially of, and comprising the five IL23R region
SNPs rs7530511, rs11465804, rs10889671, rs11209026, and rs1857292
(see Table 5), combinations consisting of, consisting essentially
of, and comprising the three IL23R region SNPs rs7530511,
rs10889671, and rs11209026 (see Table 6), and combinations
consisting of, consisting essentially of, and comprising the twelve
IL23R region SNPs rs2201841, rs10489628, 10889674, rs12085634,
rs1008193, rs10889675, rs11465827, rs10889677, rs4655531,
rs11209030, rs11209031, and rs11209032 (see Table 8).
[0030] In certain exemplary embodiments, the invention provides
haplotypes consisting of, consisting essentially of, and comprising
the nine IL12B region SNPs rs2546892, rs1433048, rs6894567,
rs17860508, rs7709212, rs953861, rs6869411, rs1833754, and
rs6861600 (see Table 9), as well as each of these SNPs
individually, any combination of any of these SNPs, and
compositions and methods based on these SNP haplotypes,
combinations of SNPs, and individual SNPs, particularly methods
related to psoriasis or related pathologies (e.g., Crohn's
disease).
[0031] In further exemplary embodiments, the invention provides
haplotypes consisting of, consisting essentially of, and comprising
the nine IL12B region SNPs rs1368437, rs2082412, rs7730390,
rs3181225, rs1368439, rs3212227, rs3213120, rs3213119, and
rs2853696 (see Table 10), as well as each of these SNPs
individually, any combination of any of these SNPs, and
compositions and methods based on these SNP haplotypes,
combinations of SNPs, and individual SNPs, particularly methods
related to psoriasis or related pathologies (e.g., Crohn's
disease).
[0032] In further exemplary embodiments, the invention provides any
of the SNPs in Table 11, including each of these SNPs individually
as well as any combination of any of these SNPs, and compositions
and methods based on these SNPs in Table 11 (including any of the
SNPs individually as well as combinations thereof), particularly
methods related to psoriasis or related pathologies (e.g., Crohn's
disease). In certain embodiments, the SNP(s) include at least one
of rs1422878, rs6861600, and/or rs3212227.
[0033] In further exemplary embodiments, the invention provides
haplotypes consisting of, consisting essentially of, and comprising
the 23 IL23R region SNPs rs7530511, rs10489629, rs4655692,
rs2201841, rs11465804, rs10489628, rs1343152, rs10789229,
rs10889671, rs11209026, rs10889674, rs12085634, rs1343151,
rs1008193, rs6693831, rs10889675, rs11465827, rs10889677,
rs4655531, rs11209030, rs1857292, rs11209031, and rs11209032 (Table
7) (as well as haplotypes consisting of, consisting essentially of,
and comprising the twelve IL23R region SNPs rs2201841, rs10489628,
10889674, rs12085634, rs1008193, rs10889675, rs11465827,
rs10889677, rs4655531, rs11209030, rs11209031, and rs11209032
(Table 8); haplotypes consisting of, consisting essentially of, and
comprising the five IL23R region SNPs rs7530511, rs11465804,
rs10889671, rs11209026, and rs1857292 (Table 5); and haplotypes
consisting of, consisting essentially of, and comprising the three
IL23R region SNPs rs7530511, rs10889671, and rs11209026 (Table 6),
as well as each of these SNPs individually, any combination of any
of these SNPs, and compositions and methods based on these SNP
haplotypes, combinations of SNPs, and individual SNPs, particularly
methods related to psoriasis or related pathologies (e.g., Crohn's
disease).
[0034] In further exemplary embodiments, the invention provides
methods for diagnosis of psoriasis and related pathologies by
detecting one or more SNPs or SNP haplotypes disclosed herein,
including, for example, detecting the presence or absence of any of
the alleles of any of the SNPs that make up the haplotypes
disclosed herein. In further exemplary embodiments, the invention
provides methods for identifying an individual having an altered
(either increased or decreased) risk for developing psoriasis and
related pathologies by detecting one or more SNPs or SNP haplotypes
disclosed herein, including, for example, detecting the presence or
absence of any of the alleles of any of the SNPs that make up the
haplotypes disclosed herein. Thus, methods are provided for
determining an individual's risk for developing psoriasis and
related pathologies, among other uses, using the SNPs and SNP
haplotypes disclosed herein (including any combination of any of
these SNPs, as well as any of these SNPs in combination with other
polymorphisms).
[0035] Certain exemplary haplotypes of the invention consist of,
consist essentially of, or comprise the IL12B region SNP allele
combination of rs2546892 (G), rs1433048 (A), rs6894567 (G),
rs17860508 (C), rs7709212 (C), rs953861 (A), rs6869411 (T),
rs1833754 (T), and rs6861600 (G), particularly as non-risk
haplotypes (which may be interchangeably referred to herein as
"protective" haplotypes), as shown in Table 9. Certain other
exemplary haplotypes of the invention consist of, consist
essentially of, or comprise the IL12B region SNP allele combination
of rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225 (G),
rs1368439 (T), rs3212227 (G), rs3213120 (C), rs3213119 (G), and
rs2853696 (C), particularly as non-risk (protective) haplotypes, as
shown in Table 10.
[0036] Certain other exemplary haplotypes of the invention consist
of, consist essentially of, or comprise any of the following two
combinations of IL12B region SNP alleles, particularly as risk
haplotypes (which may be interchangeably referred to herein as a
"susceptibility" haplotypes), as shown in Table 10:
[0037] 1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (G), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (T); and
[0038] 2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (C).
[0039] Other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise any of the following three
combinations of IL12B region SNP alleles, as shown in Table 10:
[0040] 1) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (T), rs3212227 (T), rs3213120 (T), rs3213119 (T),
and rs2853696 (C);
[0041] 2) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225
(A), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (C); and
[0042] 3) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (C).
[0043] Certain other exemplary haplotypes of the invention consist
of, consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (T), rs11465804 (T), rs10889671 (A),
rs11209026 (G), and rs1857292 (T), particularly as non-risk
(protective) haplotypes, as shown in Table 5. Certain other
exemplary haplotypes of the invention consist of, consist
essentially of, or comprise the IL23R region SNP allele combination
of rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026 (A),
and rs1857292 (A), particularly as non-risk (protective)
haplotypes, as shown in Table 5. Certain other exemplary haplotypes
of the invention consist of, consist essentially of, or comprise
the IL23R region SNP allele combination of rs7530511 (C),
rs11465804 (T), rs10889671 (G), rs11209026 (G), and rs1857292 (A),
particularly as risk (susceptibility) haplotypes, as shown in Table
5. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise any of the IL23R region SNP
allele combinations shown in Table 5.
[0044] Certain other exemplary haplotypes of the invention consist
of, consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (T), rs10889671 (A), and rs11209026 (G),
particularly as non-risk (protective) haplotypes, as shown in Table
6. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (C), rs10889671 (G), and rs11209026 (A),
particularly as non-risk (protective) haplotypes, as shown in Table
6. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (C), rs10889671 (G), and rs11209026 (G),
particularly as risk (susceptibility) haplotypes, as shown in Table
6.
[0045] Certain other exemplary haplotypes of the invention consist
of, consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (T), rs10489629 (T), rs4655692 (A),
rs2201841 (A), rs11465804 (T), rs10489628 (G), rs1343152 (A),
rs10789229 (C), rs10889671 (A), rs11209026 (G), rs10889674 (T),
rs12085634 (T), rs1343151 (G), rs1008193 (C), rs6693831 (T),
rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C),
rs11209030 (C), rs1857292 (T), rs11209031 (A), and rs11209032 (G),
particularly as non-risk (protective) haplotypes, as shown in Table
7. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise the IL23R region SNP allele
combination of rs7530511 (C), rs10489629 (C), rs4655692 (G),
rs2201841 (A), rs11465804 (G), rs10489628 (G), rs1343152 (C),
rs10789229 (T), rs10889671 (G), rs11209026 (A), rs10889674 (T),
rs12085634 (T), rs1343151 (A), rs1008193 (C), rs6693831 (C),
rs10889675 (C), rs11465827 (T), rs10889677 (C), rs4655531 (C),
rs11209030 (C), rs1857292 (A), rs11209031 (A), and rs11209032 (G),
particularly as non-risk (protective) haplotypes, as shown in Table
7. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise any of the IL23R region SNP
allele combinations shown in Table 7.
[0046] Certain other exemplary haplotypes of the invention consist
of, consist essentially of, or comprise the IL23R region SNP allele
combination of rs2201841 (A), rs10489628 (G), 10889674 (T),
rs12085634 (T), rs1008193 (C), rs10889675 (C), rs11465827 (T),
rs10889677 (C), rs4655531 (C), rs11209030 (C), rs11209031 (A), and
rs11209032 (G), particularly as non-risk (protective) haplotypes,
as shown in Table 8. Certain other exemplary haplotypes of the
invention consist of, consist essentially of, or comprise the IL23R
region SNP allele combination of rs2201841 (G), rs10489628 (G),
10889674 (G), rs12085634 (T), rs1008193 (C), rs10889675 (C),
rs11465827 (T), rs10889677 (A), rs4655531 (C), rs11209030 (C),
rs11209031 (A), and rs11209032 (A), particularly as risk
(susceptibility) haplotypes, as shown in Table 8. Certain other
exemplary haplotypes of the invention consist of, consist
essentially of, or comprise the IL23R region SNP allele combination
of rs2201841 (A), rs10489628 (G), 10889674 (G), rs12085634 (A),
rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C),
rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (G),
particularly as risk (susceptibility) haplotypes, as shown in Table
8. Certain other exemplary haplotypes of the invention consist of,
consist essentially of, or comprise any of the IL23R region SNP
allele combinations shown in Table 8.
[0047] Furthermore, certain exemplary embodiments of the invention
provide methods for identifying an individual having an increased
risk of developing psoriasis by detecting one or more haplotypes,
particularly an IL12B region haplotype selected from the group
consisting of the following two risk haplotypes:
[0048] 1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (G), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (T) (see Table 10); and
[0049] 2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (C) (see Table 10).
[0050] Alternative exemplary embodiment of the invention provide
methods for identifying individuals having a decreased risk of
developing psoriasis (particularly as compared to the risk of
developing psoriasis for the IL12B risk haplotypes above) by
detecting one or more haplotypes, particularly an IL12B region
haplotype selected from the group consisting of the following two
non-risk (protective) haplotypes:
[0051] 1) rs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508
(C), rs7709212 (C), rs953861 (A), rs6869411 (T), rs1833754 (T), and
rs6861600 (G) (see Table 9); and
[0052] 2) rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225
(G), rs1368439 (T), rs3212227 (G), rs3213120 (C), rs3213119 (G),
and rs2853696 (C) (see Table 10).
[0053] Alternative exemplary embodiment of the invention provide
methods for identifying individuals having an increased risk of
developing psoriasis by detecting one or more haplotypes,
particularly an IL23R region haplotype selected from the group
consisting of the following four risk (susceptibility)
haplotypes:
[0054] 1) rs7530511 (C), rs11465804 (T), rs10889671 (G), rs11209026
(G), and rs1857292 (A) (see Table 5);
[0055] 2) rs7530511 (C), rs10889671 (G), and rs11209026 (G) (see
Table 6);
[0056] 3) rs2201841 (G), rs10489628 (G), 10889674 (G), rs12085634
(T), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (A),
rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (A)
(see Table 8); and
[0057] 4) rs2201841 (A), rs10489628 (G), 10889674 (G), rs12085634
(A), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C),
rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (G)
(see Table 8).
[0058] Alternative exemplary embodiment of the invention provide
methods for identifying individuals having a decreased risk of
developing psoriasis (particularly as compared to the risk of
developing psoriasis for the IL23R risk haplotypes above) by
detecting one or more haplotypes, particularly an IL23R region
haplotype selected from the group consisting of the following seven
non-risk (protective) haplotypes:
[0059] 1) rs7530511 (T), rs11465804 (T), rs10889671 (A), rs11209026
(G), and rs1857292 (T) (see Table 5)
[0060] 2) rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026
(A), and rs1857292 (A) (see Table 5)
[0061] 3) rs7530511 (T), rs10889671 (A), and rs11209026 (G) (see
Table 6)
[0062] 4) rs7530511 (C), rs10889671 (G), and rs11209026 (A) (see
Table 6)
[0063] 5) rs7530511 (T), rs10489629 (T), rs4655692 (A), rs2201841
(A), rs11465804 (T), rs10489628 (G), rs1343152 (A), rs10789229 (C),
rs10889671 (A), rs11209026 (G), rs10889674 (T), rs12085634 (T),
rs1343151 (G), rs1008193 (C), rs6693831 (T), rs10889675 (C),
rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C),
rs1857292 (T), rs11209031 (A), and rs11209032 (G) (see Table 7)
[0064] 6) rs7530511 (C), rs10489629 (C), rs4655692 (G), rs2201841
(A), rs11465804 (G), rs10489628 (G), rs1343152 (C), rs10789229 (T),
rs10889671 (G), rs11209026 (A), rs10889674 (T), rs12085634 (T),
rs1343151 (A), rs1008193 (C), rs6693831 (C), rs10889675 (C),
rs11465827 (T), rs10889677 (C), rs4655531 (C), rs11209030 (C),
rs1857292 (A), rs11209031 (A), and rs11209032 (G) (see Table 7);
and
[0065] 7) rs2201841 (A), rs10489628 (G), 10889674 (T), rs12085634
(T), rs1008193 (C), rs10889675 (C), rs11465827 (T), rs10889677 (C),
rs4655531 (C), rs11209030 (C), rs11209031 (A), and rs11209032 (G)
(see Table 8).
[0066] The SNPs and haplotypes provided herein can be combined with
other genetic variants, such as to increase the power to determine
psoriasis risk. For example, the SNPs and haplotypes provided
herein can be combined with any of the SNPs and haplotypes
disclosed in U.S. patent application Ser. No. 11/899,017, filed
Aug. 31, 2007 (Begovich et al.), and Cargill et al., "A large-scale
genetic association study confirms IL12B and leads to the
identification of IL23R as psoriasis risk genes", Am J Hum Genet.
2007 February; 80(2):273-90, both of which are incorporated herein
by reference in their entirety.
[0067] The nucleic acid molecules of the invention can be inserted
in an expression vector, such as to produce a variant protein in a
host cell. Thus, the present invention also provides for a vector
comprising a SNP-containing nucleic acid molecule,
genetically-engineered host cells containing the vector, and
methods for expressing a recombinant variant protein using such
host cells. In another specific embodiment, the host cells,
SNP-containing nucleic acid molecules, and/or variant proteins can
be used as targets in a method for screening and identifying
therapeutic agents or pharmaceutical compounds useful in the
treatment or prevention of psoriasis.
[0068] An aspect of this invention is a method for treating or
preventing psoriasis (including, for example, a first occurrence
and/or a recurrence of the disease), in a human subject wherein
said human subject harbors a SNP, gene, transcript, and/or encoded
protein identified in Tables 1 and 2, which method comprises
administering to said human subject a therapeutically or
prophylactically effective amount of one or more agents
counteracting the effects of the disease, such as by inhibiting (or
stimulating) the activity of a gene, transcript, and/or encoded
protein identified in Tables 1 and 2.
[0069] Another aspect of this invention is a method for identifying
an agent useful in therapeutically or prophylactically treating
psoriasis, in a human subject wherein said human subject harbors a
SNP, gene, transcript, and/or encoded protein identified in Tables
1 and 2, which method comprises contacting the gene, transcript, or
encoded protein with a candidate agent under conditions suitable to
allow formation of a binding complex between the gene, transcript,
or encoded protein and the candidate agent and detecting the
formation of the binding complex, wherein the presence of the
complex identifies said agent.
[0070] Another aspect of this invention is a method for treating or
preventing psoriasis in a human subject, in which the method
comprises:
[0071] (i) determining that said human subject harbors a SNP, gene,
transcript, and/or encoded protein identified in Tables 1 and 2,
and
[0072] (ii) administering to said subject a therapeutically or
prophylactically effective amount of one or more agents
counteracting the effects of the disease.
[0073] Another aspect of the invention is a method for identifying
a human who is likely to benefit from a drug treatment, in which
the method comprises detecting an allele of one or more SNPs
disclosed herein in said human's nucleic acids, wherein the
presence of the allele indicates that said human is likely to
benefit from the drug treatment.
[0074] Another aspect of the invention is a method for identifying
a human who is likely to benefit from a drug treatment, in which
the method comprises detecting an allele of one or more SNPs that
are in LD with one or more SNPs disclosed herein in said human's
nucleic acids, wherein the presence of the allele of the LD SNP
indicates that said human is likely to benefit from the drug
treatment.
[0075] Many other uses and advantages of the present invention will
be apparent to those skilled in the art upon review of the detailed
description of the preferred embodiments herein. Solely for clarity
of discussion, the invention is described in the sections below by
way of non-limiting examples.
[0076] Description of the Text (ASCII) File Submitted
Electronically Via EFS-Web
[0077] The following text (ASCII) file is submitted electronically
via EFS-Web as part of the instant application:
[0078] File CD000025ORD_SEQLIST.txt provides the Sequence Listing.
The Sequence Listing provides the transcript sequences (SEQ ID
NOS:1-2) and protein sequences (SEQ ID NOS:3-4) as referred to in
Table 1, and genomic sequences (SEQ ID NOS:13-20) as referred to in
Table 2, for each psoriasis-associated gene (or genomic region for
intergenic SNPs) that contains one or more SNPs of the present
invention. Also provided in the Sequence Listing are context
sequences flanking each SNP, including both transcript-based
context sequences as referred to in Table 1 (SEQ ID NOS:5-12) and
genomic-based context sequences as referred to in Table 2 (SEQ ID
NOS:21-307). In addition, the Sequence Listing provides the primer
sequences from Table 3 (SEQ ID NOS:308-541), which are
oligonucleotides that have been synthesized and used in the
laboratory to assay certain SNPs disclosed herein by
allele-specific PCR during the course of association studies to
verify the association of these SNPs with psoriasis. The context
sequences generally provide 100 bp upstream (5') and 100 bp
downstream (3') of each SNP, with the SNP in the middle of the
context sequence, for a total of 200 bp of context sequence
surrounding each SNP.
[0079] File CD000025ORD_SEQLIST.txt is 978 KB in size, and was
created on Jun. 23, 2009.
[0080] This text file is hereby incorporated by reference pursuant
to 37 CFR 1.77(b)(4).
[0081] Description of Table 1 and Table 2
[0082] Table 1 and Table 2 (both provided below) disclose the SNP
and associated gene/transcript/protein information of the present
invention. For each gene, Table 1 provides a header containing
gene, transcript and protein information, followed by a transcript
and protein sequence identifier (SEQ ID NO), and then SNP
information regarding each SNP found in that gene/transcript
including the transcript context sequence. For each gene in Table
2, a header is provided that contains gene and genomic information,
followed by a genomic sequence identifier (SEQ ID NO) and then SNP
information regarding each SNP found in that gene, including the
genomic context sequence.
[0083] Note that SNP markers may be included in both Table 1 and
Table 2; Table 1 presents the SNPs relative to their transcript
sequences and encoded protein sequences, whereas Table 2 presents
the SNPs relative to their genomic sequences. In some instances
Table 2 may also include, after the last gene sequence, genomic
sequences of one or more intergenic regions, as well as SNP context
sequences and other SNP information for any SNPs that lie within
these intergenic regions. Additionally, in either Table 1 or 2 a
"Related Interrogated SNP" may be listed following a SNP which is
determined to be in LD with that interrogated SNP according to the
given Power value. SNPs can be readily cross-referenced between all
Tables based on their Celera hCV (or, in some instances, hDV)
identification numbers and/or public rs identification numbers, and
to the Sequence Listing based on their corresponding SEQ ID
NOs.
[0084] The gene/transcript/protein information includes: [0085] a
gene number (1 through n, where n=the total number of genes in the
Table), [0086] a gene symbol, along with an Entrez gene
identification number (Entrez Gene database, National Center for
Biotechnology Information (NCBI), National Library of Medicine,
National Institutes of Health) [0087] a gene name, [0088] an
accession number for the transcript (e.g., RefSeq NM number, or a
Celera hCT identification number if no RefSeq NM number is
available) (Table 1 only), [0089] an accession number for the
protein (e.g., RefSeq NP number, or a Celera hCP identification
number if no RefSeq NP number is available) (Table 1 only), [0090]
the chromosome number of the chromosome on which the gene is
located, [0091] an OMIM ("Online Mendelian Inheritance in Man"
database, Johns Hopkins University/NCBI) public reference number
for the gene, and OMIM information such as alternative gene/protein
name(s) and/or symbol(s) in the OMIM entry.
[0092] Note that, due to the presence of alternative splice forms,
multiple transcript/protein entries may be provided for a single
gene entry in Table 1; i.e., for a single Gene Number, multiple
entries may be provided in series that differ in their
transcript/protein information and sequences.
[0093] Following the gene/transcript/protein information is a
transcript context sequence (Table 1), or a genomic context
sequence (Table 2), for each SNP within that gene.
[0094] After the last gene sequence, Table 2 may include additional
genomic sequences of intergenic regions (in such instances, these
sequences are identified as "Intergenic region:" followed by a
numerical identification number), as well as SNP context sequences
and other SNP information for any SNPs that lie within each
intergenic region (such SNPs are identified as "INTERGENIC" for SNP
type).
[0095] Note that the transcript, protein, and transcript-based SNP
context sequences are all provided in the Sequence Listing. The
transcript-based SNP context sequences are provided in both Table 1
and also in the Sequence Listing. The genomic and genomic-based SNP
context sequences are provided in the Sequence Listing. The
genomic-based SNP context sequences are provided in both Table 2
and in the Sequence Listing. SEQ ID NOs are indicated in Table 1
for the transcript-based context sequences (SEQ ID NOS:5-12); SEQ
ID NOs are indicated in Table 2 for the genomic-based context
sequences (SEQ ID NOS:21-307).
[0096] The SNP information includes: [0097] Context sequence (taken
from the transcript sequence in Table 1, the genomic sequence in
Table 2) with the SNP represented by its IUB code, including 100 bp
upstream (5') of the SNP position plus 100 bp downstream (3') of
the SNP position (the transcript-based SNP context sequences in
Table 1 are provided in the Sequence Listing as SEQ ID NOS:5-12;
the genomic-based SNP context sequences in Table 2 are provided in
the Sequence Listing as SEQ ID NOS:21-307). [0098] Celera hCV
internal identification number for the SNP (in some instances, an
"hDV" number is given instead of an "hCV" number). [0099] The
corresponding public identification number for the SNP, the rs
number. [0100] "SNP Chromosome Position" indicates the nucleotide
position of the SNP along the entire sequence of the chromosome as
provided in NCBI Genome Build 36. [0101] SNP position (nucleotide
position of the SNP within the given transcript sequence (Table 1)
or within the given genomic sequence (Table 2)). [0102] "Related
Interrogated SNP" is the interrogated SNP with which the listed SNP
is in LD at the given value of Power. [0103] SNP source (may
include any combination of one or more of the following five codes,
depending on which internal sequencing projects and/or public
databases the SNP has been observed in: "Applera"=SNP observed
during the re-sequencing of genes and regulatory regions of 39
individuals, "Celera"=SNP observed during shotgun sequencing and
assembly of the Celera human genome sequence, "Celera
Diagnostics"=SNP observed during re-sequencing of nucleic acid
samples from individuals who have a disease, "dbSNP"=SNP observed
in the dbSNP public database, "HGBASE"=SNP observed in the HGBASE
public database, "HGMD"=SNP observed in the Human Gene Mutation
Database (HGMD) public database, "HapMap"=SNP observed in the
International HapMap Project public database, "CSNP"=SNP observed
in an internal Applied Biosystems (Foster City, Calif.) database of
coding SNPS (cSNPs).
[0104] Note that multiple "Applera" source entries for a single SNP
indicate that the same SNP was covered by multiple overlapping
amplification products and the re-sequencing results (e.g.,
observed allele counts) from each of these amplification products
is being provided. [0105] Population/allele/allele count
information in the format of
[population1(first_allele,count|second_allele,count)population2-
(first_allele,count|second_allele,count) total (first_allele,total
count|second_allele,total count)]. The information in this field
includes populations/ethnic groups in which particular SNP alleles
have been observed ("cau"=Caucasian, "his"=Hispanic, "chn"=Chinese,
and "afr"=African-American, "jpn"=Japanese, "ind"=Indian,
"mex"=Mexican, "ain"="American Indian, "cra"=Celera donor,
"no_pop"=no population information available), identified SNP
alleles, and observed allele counts (within each population group
and total allele counts), where available ["-" in the allele field
represents a deletion allele of an insertion/deletion ("indel")
polymorphism (in which case the corresponding insertion allele,
which may be comprised of one or more nucleotides, is indicated in
the allele field on the opposite side of the "|"); "-" in the count
field indicates that allele count information is not available].
For certain SNPs from the public dbSNP database, population/ethnic
information is indicated as follows (this population information is
publicly available in dbSNP): "HISP1"=human individual DNA
(anonymized samples) from 23 individuals of self-described HISPANIC
heritage; "PAC1"=human individual DNA (anonymized samples) from 24
individuals of self-described PACIFIC RIM heritage; "CAUC1"=human
individual DNA (anonymized samples) from 31 individuals of
self-described CAUCASIAN heritage; "AFR1"=human individual DNA
(anonymized samples) from 24 individuals of self-described
AFRICAN/AFRICAN AMERICAN heritage; "P1"=human individual DNA
(anonymized samples) from 102 individuals of self-described
heritage; "PA130299515"; "SC_12_A"=SANGER 12 DNAs of Asian origin
from Corielle cell repositories, 6 of which are male and 6 female;
"SC_12_C"=SANGER 12 DNAs of Caucasian origin from Corielle cell
repositories from the CEPH/UTAH library, six male and six female;
"SC_12_AA"=SANGER 12 DNAs of African-American origin from Corielle
cell repositories 6 of which are male and 6 female;
"SC_95_C"=SANGER 95 DNAs of Caucasian origin from Corielle cell
repositories from the CEPH/UTAH library; and
"SC_12_CA"=Caucasians--12 DNAs from Corielle cell repositories that
are from the CEPH/UTAH library, six male and six female.
[0106] Note that for SNPs of "Applera" SNP source, genes/regulatory
regions of 39 individuals (20 Caucasians and 19 African Americans)
were re-sequenced and, since each SNP position is represented by
two chromosomes in each individual (with the exception of SNPs on X
and Y chromosomes in males, for which each SNP position is
represented by a single chromosome), up to 78 chromosomes were
genotyped for each SNP position. Thus, the sum of the
African-American ("afr") allele counts is up to 38, the sum of the
Caucasian allele counts ("cau") is up to 40, and the total sum of
all allele counts is up to 78.
[0107] Note that semicolons separate population/allele/count
information corresponding to each indicated SNP source; i.e., if
four SNP sources are indicated, such as "Celera," "dbSNP,"
"HGBASE," and "HGMD," then population/allele/count information is
provided in four groups which are separated by semicolons and
listed in the same order as the listing of SNP sources, with each
population/allele/count information group corresponding to the
respective SNP source based on order; thus, in this example, the
first population/allele/count information group would correspond to
the first listed SNP source (Celera) and the third
population/allele/count information group separated by semicolons
would correspond to the third listed SNP source (HGBASE); if
population/allele/count information is not available for any
particular SNP source, then a pair of semicolons is still inserted
as a place-holder in order to maintain correspondence between the
list of SNP sources and the corresponding listing of
population/allele/count information. [0108] SNP type (e.g.,
location within gene/transcript and/or predicted functional effect)
["MISSENSE MUTATION"=SNP causes a change in the encoded amino acid
(i.e., a non-synonymous coding SNP); "SILENT MUTATION"=SNP does not
cause a change in the encoded amino acid (i.e., a synonymous coding
SNP); "STOP CODON MUTATION"=SNP is located in a stop codon;
"NONSENSE MUTATION"=SNP creates or destroys a stop codon; "UTR
5"=SNP is located in a 5' UTR of a transcript; "UTR 3"=SNP is
located in a 3' UTR of a transcript; "PUTATIVE UTR 5"=SNP is
located in a putative 5' UTR; "PUTATIVE UTR 3"=SNP is located in a
putative 3' UTR; "DONOR SPLICE SITE"=SNP is located in a donor
splice site (5' intron boundary); "ACCEPTOR SPLICE SITE"=SNP is
located in an acceptor splice site (3' intron boundary); "CODING
REGION"=SNP is located in a protein-coding region of the
transcript; "EXON"=SNP is located in an exon; "INTRON"=SNP is
located in an intron; "hmCS"=SNP is located in a human-mouse
conserved segment; "TFBS"=SNP is located in a transcription factor
binding site; "UNKNOWN"=SNP type is not defined; "INTERGENIC"=SNP
is intergenic, i.e., outside of any gene boundary]. [0109] Protein
coding information (Table 1 only), where relevant, in the format of
[protein SEQ ID NO, amino acid position, (amino acid-1, codon1)
(amino acid-2, codon2)]. The information in this field includes SEQ
ID NO of the encoded protein sequence, position of the amino acid
residue within the protein identified by the SEQ ID NO that is
encoded by the codon containing the SNP, amino acids (represented
by one-letter amino acid codes) that are encoded by the alternative
SNP alleles (in the case of stop codons, "X" is used for the
one-letter amino acid code), and alternative codons containing the
alternative SNP nucleotides which encode the amino acid residues
(thus, for example, for missense mutation-type SNPs, at least two
different amino acids and at least two different codons are
generally indicated; for silent mutation-type SNPs, one amino acid
and at least two different codons are generally indicated, etc.).
In instances where the SNP is located outside of a protein-coding
region (e.g., in a UTR region), "None" is indicated following the
protein SEQ ID NO.
[0110] Description of Table 3
[0111] Table 3 provides sequences (SEQ ID NOS:308-541) of primers
that may be used to assay the SNPs disclosed herein by
allele-specific PCR or other methods, such as for uses related to
psoriasis and other autoinflammatory diseases.
[0112] Table 3 provides the following: [0113] the column labeled
"Marker" provides an hCV identification number for each SNP that
can be detected using the corresponding primers. [0114] the column
labeled "Alleles" designates the two alternative alleles (i.e.,
nucleotides) at the SNP site. These alleles are targeted by the
allele-specific primers (the allele-specific primers are shown as
Primer 1 and Primer 2). Note that alleles may be presented in Table
3 based on a different orientation (i.e., the reverse complement)
relative to how the same alleles are presented in Tables 1-2.
[0115] the column labeled "Primer 1 (Allele-Specific Primer)"
provides an allele-specific primer that is specific for an allele
designated in the "Alleles" column. [0116] the column labeled
"Primer 2 (Allele-Specific Primer)" provides an allele-specific
primer that is specific for the other allele designated in the
"Alleles" column. [0117] the column labeled "Common Primer"
provides a common primer that is used in conjunction with each of
the allele-specific primers (i.e., Primer 1 and Primer 2) and which
hybridizes at a site away from the SNP position.
[0118] All primer sequences are given in the 5' to 3'
direction.
[0119] Each of the nucleotides designated in the "Alleles" column
matches or is the reverse complement of (depending on the
orientation of the primer relative to the designated allele) the 3'
nucleotide of the allele-specific primer (i.e., either Primer 1 or
Primer 2) that is specific for that allele.
[0120] Description of Table 4
[0121] Table 4 provides a list of LD SNPs that are related to and
derived from certain interrogated SNPs. The interrogated SNPs,
which are shown in column 1 (which indicates the hCV identification
numbers of each interrogated SNP) and column 2 (which indicates the
public rs identification numbers of each interrogated SNP) of Table
4, are statistically significantly associated with psoriasis, as
described and shown herein, particularly in Tables 5-11 and in the
Examples section below. The LD SNPs are provided as an example of
SNPs which can also serve as markers for disease association based
on their being in LD with an interrogated SNP. The criteria and
process of selecting such LD SNPs, including the calculation of the
r.sup.2 value and the r.sup.2 threshold value, are described in
Example 3, below.
[0122] In Table 4, the column labeled "Interrogated SNP" presents
each marker as identified by its unique hCV identification number.
The column labeled "Interrogated rs" presents the publicly known rs
identification number for the corresponding hCV number. The column
labeled "LD SNP" presents the hCV numbers of the LD SNPs that are
derived from their corresponding interrogated SNPs. The column
labeled "LD SNP rs" presents the publicly known rs identification
number for the corresponding hCV number. The column labeled "Power"
presents the level of power where the r.sup.2 threshold is set. For
example, when power is set at 0.51, the threshold r.sup.2 value
calculated therefrom is the minimum r.sup.2 that an LD SNP must
have in reference to an interrogated SNP, in order for the LD SNP
to be classified as a marker capable of being associated with a
disease phenotype at greater than 51% probability. The column
labeled "Threshold r.sup.2" presents the minimum value of r.sup.2
that an LD SNP must meet in reference to an interrogated SNP in
order to qualify as an LD SNP. The column labeled "r.sup.2"
presents the actual r.sup.2 value of the LD SNP in reference to the
interrogated SNP to which it is related.
[0123] Description of Tables 5-11
[0124] Tables 5-11 provide the results of statistical analyses for
SNPs disclosed in Tables 1 and 2 (SNPs can be cross-referenced
between all the tables herein based on their hCV and/or rs
identification numbers). The results shown in Tables 5-11 provide
support for the association of these SNPs with psoriasis.
[0125] Tables 5-8 are further described in Example 1 below
(identification and analysis of haplotypes in the IL23R region
associated with psoriasis).
[0126] Table 5 provides information for haplotypes based on the
following 5 IL23R region SNPs: rs7530511, rs11465804, rs10889671,
rs11209026, and rs1857292. For the psoriasis risk (susceptibility)
haplotype rs7530511 (C), rs11465804 (T), rs10889671 (G), rs11209026
(G), rs1857292 (A), the naive odds ratio (OR) was 1.391
(P.sub.comb=0.000000648). For the psoriasis non-risk (protective)
haplotype rs7530511 (T), rs11465804 (T), rs10889671 (A), rs11209026
(G), rs1857292 (T), the naive odds ratio (OR) was 0.752
(P.sub.comb=0.00356). For the psoriasis non-risk (protective)
haplotype rs7530511 (C), rs11465804 (G), rs10889671 (G), rs11209026
(A), rs1857292 (A), the naive odds ratio (OR) was 0.599
(P.sub.comb=0.0000399).
[0127] Table 6 provides information for haplotypes based on the
following 3 IL23R region SNPs: rs7530511, rs10889671, and
rs11209026. For the psoriasis risk (susceptibility) haplotype
rs7530511 (C), rs10889671 (G), rs112090 (G), the naive odds ratio
(OR) was 1.436 (P.sub.comb=0.000000384). For the psoriasis non-risk
(protective) haplotype rs7530511 (T), rs10889671 (A), rs112090 (G),
the naive odds ratio (OR) was 0.757 (P.sub.comb=0.0012). For the
psoriasis non-risk (protective) haplotype rs7530511 (C), rs10889671
(G), rs112090 (A), the naive odds ratio (OR) was 0.588
(P.sub.comb=0.00000974).
[0128] Table 7 provides information for haplotypes based on the
following 23 IL23R region SNPs: rs7530511, rs10489629, rs4655692,
rs2201841, rs11465804, rs10489628, rs1343152, rs10789229,
rs10889671, rs11209026, rs10889674, rs12085634, rs1343151,
rs1008193, rs6693831, rs10889675, rs11465827, rs10889677,
rs4655531, rs11209030, rs1857292, rs11209031, and rs11209032.
[0129] Table 8 provides information for haplotypes based on the
following 12 IL23R region SNPs: rs2201841, rs10489628, 10889674,
rs12085634, rs1008193, rs10889675, rs11465827, rs10889677,
rs4655531, rs11209030, rs11209031, and rs11209032.
[0130] Tables 9-11 are further described in Example 2 below
(identification and analysis of haplotypes and individual SNPs in
the IL12B region associated with psoriasis).
[0131] Table 9 provides information for haplotypes based on the
following 9 IL12B region SNPs: rs2546892, rs1433048, rs6894567,
rs17860508, rs7709212, rs953861, rs6869411, rs1833754, and
rs6861600.
[0132] Table 10 provides information for haplotypes based on the
following 9 IL12B region SNPs: rs1368437, rs2082412, rs7730390,
rs3181225, rs1368439, rs3212227, rs3213120, rs3213119, and
rs2853696.
[0133] Table 11 provides 105 SNPs in the IL12B region that have
been identified as being associated with psoriasis risk
(p-value<0.05). In Table 11, the column labeled "Genotyped or
Imputed" indicates whether the data provided for the given SNP was
derived from genotyping of psoriasis samples or from imputation.
See Example 2 below for further information regarding Table 11.
[0134] Tables 5 and 6 indicate case and control counts, with case
and control frequencies in parentheses. Tables 9 and 10 indicate
case and control frequencies, with case and control counts in
parentheses. Table 7 only indicates case and control counts (not
frequencies). Table 8 only indicates case and control counts in the
upper portion of the table, and only indicates case and control
frequencies in the lower portion of the table. Table 11 indicates
case and control frequencies.
[0135] In Tables 9 and 10, each of the nine nucleotides of each
haplotype respectively correspond to each of the nine SNPs listed
in the column labeled "SNP set".
[0136] In Tables 9 and 10, "S0048", "50056A", and "A0019" indicate
independent sample sets (i.e., study populations). Specifically,
"S0048", "50056A", and "A0019" correspond to "Sample Set 1",
"Sample Set 2", and "Sample Set 3", respectively, which are
described below in Example 1.
[0137] Throughout Tables 5-11, "P", "P-value", or "Hap.P" refers to
the p-value for the given haplotype (or individual SNP in Table
11).
[0138] In Tables 5-6 and 9-10, "Comb P" or P.sub.comb refers to
p-values across independent studies (sample sets).
[0139] In Tables 9 and 10, "Global" refers to p-values for all
haplotypes combined together within a study (sample set), and
"Global Comb P" refers to the p-value for all haplotypes combined
together across independent studies (sample sets).
[0140] In Table 10, "Other" refers to other haplotypes not
listed.
[0141] Throughout Tables 5-11, "OR" refers to the odds ratio
("OR95l" and "OR95u" in Table 11 refer to the lower and upper 95%
confidence intervals, respectively, for the odds ratio). Odds
ratios (OR) that are greater than one indicate that a given allele
or haplotype is a risk allele/haplotype associated with an
increased risk for a given disease such as psoriasis (which may
also be referred to as a "susceptibility" allele/haplotype),
whereas odds ratios that are less than one indicate that a given
allele or haplotype is a non-risk allele/haplotype associated with
a decreased risk for a given disease such as psoriasis (which may
also be referred to as a "protective" allele/haplotype),
particularly as compared to the disease risk for the risk
allele/haplotype. For a given risk allele, the other alternative
allele at the SNP position (which can be derived from the
information provided in Tables 1-2, for example) may be considered
a non-risk allele. For a given non-risk allele, the other
alternative allele at the SNP position may be considered a risk
allele.
[0142] Thus, with respect to disease risk (e.g., psoriasis), if the
risk estimate (odds ratio or hazard ratio) for a particular allele
at a SNP position is greater than one, this indicates that an
individual with this particular allele has a higher risk for the
disease than an individual who has the other allele at the SNP
position. In contrast, if the risk estimate (odds ratio or hazard
ratio) for a particular allele is less than one, this indicates
that an individual with this particular allele has a reduced risk
for the disease compared with an individual who has the other
allele at the SNP position.
[0143] With respect to drug response (e.g., response to an
anti-IL12 and/or an anti-IL23 therapy), if the risk estimate (odds
ratio or hazard ratio) of those treated with the drug (e.g., an
anti-IL12 and/or an anti-IL23 antibody) compared with those treated
with a placebo within a particular genotype is less than one, this
indicates that an individual with this particular genotype would
benefit from the drug (an odds ratio or hazard ratio equal to one
would indicate that the drug has no effect). As used herein, the
term "benefit" (with respect to a preventive or therapeutic drug
treatment) is defined as achieving a reduced risk for a disease
that the drug is intended to treat or prevent (e.g., psoriasis or a
related pathology such as Crohn's disease) by administrating the
drug treatment, compared with the risk for the disease in the
absence of receiving the drug treatment (or receiving a placebo in
lieu of the drug treatment) for the same genotype.
DETAILED DESCRIPTION OF THE INVENTION
[0144] The present invention provides SNPs associated with
autoinflammatory diseases such as psoriasis. The present invention
further provides nucleic acid molecules containing these SNPs,
methods and reagents for the detection of the SNPs disclosed
herein, uses of these SNPs for the development of detection
reagents, and assays or kits that utilize such reagents. The SNPs
disclosed herein are useful for diagnosing, prognosing, screening
for, and evaluating predisposition to psoriasis and related
pathologies (e.g., Crohn's disease and other autoinflammatory
diseases) in humans, as well as for predicting an individual's
responsiveness to therapies used to treat psoriasis and related
pathologies. Furthermore, such SNPs and their encoded products are
useful targets for the development of therapeutic and preventive
agents.
[0145] A large number of SNPs have been identified from
re-sequencing DNA from 39 individuals, and they are indicated as
"Applera" SNP source in Tables 1-2. Their allele frequencies
observed in each of the Caucasian and African-American ethnic
groups are provided. Additional SNPs included herein were
previously identified during "shotgun" sequencing and assembly of
the human genome, and they are indicated as "Celera" SNP source in
Tables 1 and 2. Furthermore, the information provided in Tables 1
and 2, particularly the allele frequency information obtained from
39 individuals and the identification of the precise position of
each SNP within each gene/transcript, allows haplotypes (i.e.,
groups of SNPs that are co-inherited) to be readily inferred. The
present invention encompasses SNP haplotypes, as well as individual
SNPs.
[0146] Thus, the present invention provides individual SNPs
associated with psoriasis, as well as combinations of SNPs and
haplotypes, polymorphic/variant transcript sequences (SEQ ID
NOS:1-2) and genomic sequences (SEQ ID NOS:13-20) containing SNPs,
encoded amino acid sequences (SEQ ID NOS:3-4), and both
transcript-based SNP context sequences (SEQ ID NOS:5-12) and
genomic-based SNP context sequences (SEQ ID NOS:21-307) (transcript
sequences, protein sequences, and transcript-based SNP context
sequences are provided in Table 1 and the Sequence Listing; genomic
sequences and genomic-based SNP context sequences are provided in
Table 2 and the Sequence Listing), methods of detecting these
polymorphisms in a test sample, methods of determining the risk of
an individual of having or developing psoriasis, methods of
determining if an individual is likely to respond to a particular
treatment (particularly for treating or preventing psoriasis),
methods of screening for compounds useful for treating disorders
associated with a variant gene/protein such as psoriasis, compounds
identified by these screening methods, methods of using the
disclosed SNPs to select a treatment/preventive strategy or
therapeutic agent, methods of treating or preventing a disorder
associated with a variant gene/protein, and methods of using the
SNPs of the present invention for human identification.
[0147] The present invention further provides methods for selecting
or formulating a treatment regimen (e.g., methods for determining
whether or not to administer treatment to an individual having
psoriasis, or who is at risk for developing psoriasis in the
future, or who has previously had psoriasis, methods for selecting
a particular treatment regimen such as dosage and frequency of
administration, or a particular form/type of drug such as a
particular pharmaceutical formulation or compound, etc.), and
methods for determining the likelihood of experiencing toxicity or
other undesirable side effects from a drug treatment, etc. The
present invention also provides methods for selecting individuals
to whom a therapeutic agent will be administered based on the
individual's genotype, and methods for selecting individuals for a
clinical trial of a therapeutic agent based on the genotypes of the
individuals (e.g., selecting individuals to participate in the
trial who are most likely to respond positively from the drug
treatment and/or excluding individuals from the trial who are
unlikely to respond positively from the drug treatment based on
their SNP genotype(s), or selecting individuals who are unlikely to
respond positively to a particular drug based on their SNP
genotype(s) to participate in a clinical trial of another type of
drug that may benefit them).
[0148] The present invention provides novel SNPs associated with
psoriasis, as well as SNPs that were previously known in the art,
but were not previously known to be associated with psoriasis.
Accordingly, the present invention provides novel compositions and
methods based on the novel SNPs disclosed herein, and also provides
novel methods of using the known, but previously unassociated, SNPs
in methods relating to evaluating an individual's likelihood of
having or developing psoriasis, predicting the likelihood of an
individual experiencing a recurrence of psoriasis, prognosing the
severity of psoriasis in an individual, or prognosing an
individual's recovery from psoriasis, and methods relating to
evaluating an individual's likelihood of responding to a drug
treatment. In Tables 1 and 2, known SNPs are identified based on
the public database in which they have been observed, which is
indicated as one or more of the following SNP types: "dbSNP"=SNP
observed in dbSNP, "HGBASE"=SNP observed in HGBASE, and "HGMD"=SNP
observed in the Human Gene Mutation Database (HGMD).
[0149] Particular SNP alleles of the present invention can be
associated with either an increased risk of having or developing
psoriasis or increased likelihood of responding to a drug
treatment, or a decreased risk of having or developing psoriasis or
decreased likelihood of responding to a drug treatment. Thus,
whereas certain SNPs (or their encoded products) can be assayed to
determine whether an individual possesses a SNP allele that is
indicative of an increased risk of having or developing psoriasis
or increased likelihood of responding to a drug treatment, other
SNPs (or their encoded products) can be assayed to determine
whether an individual possesses a SNP allele that is indicative of
a decreased risk of having or developing psoriasis or decreased
likelihood of responding to a drug treatment. Similarly, particular
SNP alleles of the present invention can be associated with either
an increased or decreased likelihood of having a recurrence of
psoriasis, of fully recovering from psoriasis, of experiencing
toxic effects from a particular treatment or therapeutic compound,
etc. The term "altered" may be used herein to encompass either of
these two possibilities (e.g., an increased or a decreased
risk/likelihood). SNP alleles that are associated with a decreased
risk of having or developing psoriasis may be referred to as
"protective" alleles, and SNP alleles that are associated with an
increased risk of having or developing psoriasis may be referred to
as "susceptibility" alleles, "risk" alleles, or "risk factors".
[0150] Those skilled in the art will readily recognize that nucleic
acid molecules may be double-stranded molecules and that reference
to a particular site on one strand refers, as well, to the
corresponding site on a complementary strand. In defining a SNP
position, SNP allele, or nucleotide sequence, reference to an
adenine, a thymine (uridine), a cytosine, or a guanine at a
particular site on one strand of a nucleic acid molecule also
defines the thymine (uridine), adenine, guanine, or cytosine
(respectively) at the corresponding site on a complementary strand
of the nucleic acid molecule. Thus, reference may be made to either
strand in order to refer to a particular SNP position, SNP allele,
or nucleotide sequence. Probes and primers, may be designed to
hybridize to either strand and SNP genotyping methods disclosed
herein may generally target either strand. Throughout the
specification, in identifying a SNP position, reference is
generally made to the protein-encoding strand, only for the purpose
of convenience.
[0151] References to variant peptides, polypeptides, or proteins of
the present invention include peptides, polypeptides, proteins, or
fragments thereof, that contain at least one amino acid residue
that differs from the corresponding amino acid sequence of the
art-known peptide/polypeptide/protein (the art-known protein may be
interchangeably referred to as the "wild-type," "reference," or
"normal" protein). Such variant peptides/polypeptides/proteins can
result from a codon change caused by a nonsynonymous nucleotide
substitution at a protein-coding SNP position (i.e., a missense
mutation) disclosed by the present invention. Variant
peptides/polypeptides/proteins of the present invention can also
result from a nonsense mutation (i.e., a SNP that creates a
premature stop codon, a SNP that generates a read-through mutation
by abolishing a stop codon), or due to any SNP disclosed by the
present invention that otherwise alters the structure, function,
activity, or expression of a protein, such as a SNP in a regulatory
region (e.g. a promoter or enhancer) or a SNP that leads to
alternative or defective splicing, such as a SNP in an intron or a
SNP at an exon/intron boundary. As used herein, the terms
"polypeptide," "peptide," and "protein" are used
interchangeably.
[0152] As used herein, an "allele" may refer to a nucleotide at a
SNP position (wherein at least two alternative nucleotides are
present in the population at the SNP position, in accordance with
the inherent definition of a SNP) or may refer to an amino acid
residue that is encoded by the codon which contains the SNP
position (where the alternative nucleotides that are present in the
population at the SNP position form alternative codons that encode
different amino acid residues). An "allele" may also be referred to
herein as a "variant". Also, an amino acid residue that is encoded
by a codon containing a particular SNP may simply be referred to as
being encoded by the SNP.
[0153] A phrase such as "as represented by", "as shown by", "as
symbolized by", or "as designated by" may be used herein to refer
to a SNP within a sequence (e.g., a polynucleotide context sequence
surrounding a SNP), such as in the context of "a polymorphism as
represented by position 101 of SEQ ID NO:X or its complement".
Typically, the sequence surrounding a SNP may be recited when
referring to a SNP, however the sequence is not intended as a
structural limitation beyond the specific SNP position itself.
Rather, the sequence is recited merely as a way of referring to the
SNP (in this example, "SEQ ID NO:X or its complement" is recited in
order to refer to the SNP located at position 101 of SEQ ID NO:X,
but SEQ ID NO:X or its complement is not intended as a structural
limitation beyond the specific SNP position itself). In other
words, it is recognized that the context sequence of SEQ ID NO:X in
this example may contain one or more polymorphic nucleotide
positions outside of position 101 and therefore an exact match over
the full-length of SEQ ID NO:X is irrelevant since SEQ ID NO:X is
only meant to provide context for referring to the SNP at position
101 of SEQ ID NO:X. Likewise, the length of the context sequence is
also irrelevant (100 nucleotides on each side of a SNP position has
been arbitrarily used in the present application as the length for
context sequences merely for convenience and because 201
nucleotides of total length is expected to provide sufficient
uniqueness to unambiguously identify a given nucleotide sequence).
Thus, since a SNP is a variation at a single nucleotide position,
it is customary to refer to context sequence (e.g., SEQ ID NO:X in
this example) surrounding a particular SNP position in order to
uniquely identify and refer to the SNP. Alternatively, a SNP can be
referred to by a unique identification number such as a public "rs"
identification number or an internal "hCV" identification number,
such as provided herein for each SNP (e.g., in Tables 1-2).
[0154] As used herein, the term "benefit" (with respect to a
preventive or therapeutic drug treatment) is defined as achieving a
reduced risk for a disease that the drug is intended to treat or
prevent (e.g., psoriasis) by administrating the drug treatment,
compared with the risk for the disease in the absence of receiving
the drug treatment (or receiving a placebo in lieu of the drug
treatment) for the same genotype. The term "benefit" may be used
herein interchangeably with terms such as "respond positively" or
"positively respond".
[0155] As used herein, the terms "drug" and "therapeutic agent" are
used interchangeably, and may include, but are not limited to,
small molecule compounds, biologics (e.g., antibodies, proteins,
protein fragments, fusion proteins, glycoproteins, etc.), nucleic
acid agents (e.g., antisense, RNAi/siRNA, and microRNA molecules,
etc.), vaccines, etc., which may be used for therapeutic and/or
preventive treatment of a disease (e.g., psoriasis or Crohn's
disease).
[0156] As used herein, the term "related pathologies" (e.g., in the
context of "psoriasis and related pathologies") includes
inflammatory and autoimmune disorders (collectively referred to
herein as "autoinflammatory" diseases/disorders) such as
inflammatory bowel disease (IBD) (including Crohn's disease, which
further includes both adult and pediatric Crohn's disease, and
ulcerative colitis) and other chronic inflammatory disorders,
atopic dermatitis, multiple sclerosis, rheumatoid arthritis,
ankylosing spondylitis (AS), celiac disease, Graves' disease
(including Graves' ophthalmopathy (GO) and Graves' disease without
opthalmopathy), and Barrett's esophagus.
[0157] In addition to autoinflammatory diseases, it is also
specifically contemplated that the SNPs and haplotypes of the
invention may also have utilities with respect to an individual's
response to infectious diseases (e.g., mycobacterial infections
such as tuberculosis and leprosy, as well as Chagas' disease
cardiomyopathy and fatal cerebral malaria), as well as other
disorders such as hypertension and stroke. For example, the
exemplary SNPs and haplotypes of the invention may be used for
determining an individual's susceptibility to these disorders (or
the individual's immune response to infectious agents), as well as
psoriasis, Crohn's disease, and related pathologies (such as the
pathologies identified in the preceding paragraph). For the role of
IL12B in hypertension and stroke, see Timasheva et al.,
"Association of interleukin-6, interleukin-12, and interleukin-10
gene polymorphisms with essential hypertension in Tatars from
Russia", Biochem Genet. 2008 February; 46(1-2):64-74. For the role
of IL12B in mycobacterial infections such as tuberculosis and
leprosy, see Morahan et al., "Association of variants in the IL12B
gene with leprosy and tuberculosis", Tissue Antigens. 2007 April;
69 Suppl 1:234-6. For the role of IL12B in Chagas' disease
cardiomyopathy, see Zafra et al., "Polymorphism in the 3' UTR of
the IL12B gene is associated with Chagas' disease cardiomyopathy",
Microbes Infect. 2007 July; 9(9):1049-52. For the role of IL12B in
fatal cerebral malaria, see Morahan et al., "A promoter
polymorphism in the gene encoding interleukin-12 p40 (IL12B) is
associated with mortality from cerebral malaria and with reduced
nitric oxide production", Genes Immun. 2002 November;
3(7):414-8.
[0158] The following references further describe the roles of IL12B
and/or IL23R in psoriasis, Crohn's disease, and other
autoinflammatory diseases, as well as in response to infectious
diseases: Schrodi (2008) "Genome-wide association scan in
psoriasis: new insights into chronic inflammatory disease", Expert
Rev. Clin. Immunol. 4(5); Duffin et al., "Genetic variations in
cytokines and cytokine receptors associated with psoriasis found by
genome-wide association", J Invest Dermatol. 2009 April;
129(4):827-33; Nair et al (2009) "Genome-wide scan reveals
association of psoriasis with IL-23 and NF-kappaB pathways". Nat
Genet 41(2):199-204; Brown (2009) "Genetics and the pathogenesis of
ankylosing spondylitis". Curr Opin Rheumatol 21(4):318-323; Elder
(2009) "Genome-wide association scan yields new insights into the
immunopathogenesis of psoriasis". Genes Immun 10(3):201-209;
Abraham et al. (2009) "Interleukin-23/Th17 pathways and
inflammatory bowel disease". Inflamm Bowel Dis. February 27 [Epub];
Gee et al (2009) "The IL-12 family of cytokines in infection,
inflammation and autoimmune disorders". Inflamm Allergy Drug
Targets. 8(1):40-52; Kauffman et al. (2004) "A Phase I study
evaluating the safety, pharmacokinetics, and clinical response of a
human IL-12 p40 antibody in subjects with plaque psoriasis". J Inv
Dermat 123:1037-1044; Krueger et al. (2007) "A human
interleukin-12/23 monoclonal antibody for the treatment of
psoriasis". N Engl J Med 356:580-592; Mannon et al. (2004)
"Anti-interleukin-12 antibody for active Crohn's disease". N Engl J
Med 351: 2069-2079; and Park et al. (2005) "A distinct lineage of
CD4 T cells regulates tissue inflammation by producing interleukin
17". Nat Immun 6:1133-1141.
[0159] IL12 and IL23 Therapeutics/Pharmacogenomics in Inflammatory
and Autoimmune Disorders
[0160] Exemplary embodiments of the invention provide SNPs in the
IL12B and IL23R regions that are particularly associated with
psoriasis (as shown in the tables and described in the Examples
section, for example). These SNPs have a variety of therapeutic and
pharmacogenomic uses related to the treatment of psoriasis, as well
as other inflammatory and automimmune disorders such as
inflammatory bowel disease (including Crohn's disease and
ulcerative colitis), atopic dermatitis, ankylosing spondylitis,
rheumatoid arthritis, multiple sclerosis, celiac disease, Graves'
disease, and Barrett's esophagus. The psoriasis-associated SNPs
provided herein may be used, for example, to determine variability
between different individuals in their response to an inflammatory
or autoimmune disease therapy (e.g., a psoriasis therapy or a
therapy for inflammatory bowel disease, Crohn's disease, ulcerative
colitis, atopic dermatitis, ankylosing spondylitis, rheumatoid
arthritis, multiple sclerosis, celiac disease, Graves' disease,
Barrett's esophagus, or other inflammatory or autoimmune disorder)
such as to predict whether an individual will respond positively to
a particular therapy, to determine the most effective therapeutic
agent (e.g., antibody, therapeutic protein, small molecule
compound, nucleic acid agent, etc.) to use to treat an individual,
to determine whether a particular therapeutic agent should or
should not be administered to an individual (e.g., by predicting
whether the individual is likely to positively respond to the
therapy or by predicting whether the individual will experience
toxic or other undesirable side effects or is unlikely to respond
to the therapy), or to determine the therapeutic regimen to use for
an individual such as the dosage or frequency of dosing of a
therapeutic agent for a particular individual. Therapeutic agents
that directly modulate (e.g., inhibit or stimulate) IL12 or IL23
may be used to treat psoriasis, Crohn's disease, or other
inflammatory/autoimmune disorders and, furthermore, therapeutic
agents that target proteins that interact with IL12 or IL23 or are
otherwise in IL12 or IL23 pathways may be used to indirectly
modulate IL12 or IL23 to thereby treat psoriasis, Crohn's disease,
or other inflammatory/autoimmune disorders. Any therapeutic agents
such as these may be used in conjunction with the SNPs provided
herein.
[0161] For example, the IL12 and IL23 psoriasis-associated SNPs
provided herein may be used to predict whether an individual will
respond positively to anti-IL12 and/or anti-IL23 antibody therapy
(e.g., anti-IL-12p40 antibodies such as ABT-874 (Abbott) and
CNTO-1275 (Centocor); see Veldman, "Targeting the p40 cytokines
interleukin (IL)-12 and IL-23 in Crohn's disease", Drug Discovery
Today: Therapeutic Strategies, Vol. 3, Issue 3, 2006, pp. 375-380,
incorporated herein by reference), especially for Crohn's disease,
psoriasis, or other autoinflammatory diseases, and/or to determine
the most effective dosages of these therapies. This facilitates
decision-making by medical practitioners, such as in deciding
whether to administer this therapy to a particular individual or
select another therapy that may be better suited to the individual,
or to use a particular dosage, dosing schedule, or to modify other
aspects of a therapeutic regimen to effectively treat the
individual, for example.
[0162] In addition to medical treatment, these uses may also be
applied, for example, in the context of clinical trials of a
therapeutic agent (e.g., a therapeutic agent that targets IL12 or
IL23 for the treatment of psoriasis, inflammatory bowel disease,
Crohn's disease, ulcerative colitis, atopic dermatitis, ankylosing
spondylitis, rheumatoid arthritis, multiple sclerosis, celiac
disease, Graves' disease, Barrett's esophagus, or other
inflammatory or autoimmune disorders), such as to include
particular individuals in a clinical trial who are predicted to
positively respond to the therapeutic agent based on the SNPs
provided herein and/or to exclude particular individuals from a
clinical trial who are predicted to not positively respond to the
therapeutic agent based on the SNPs provided herein, or to assign
individuals to a particular group within a clinical trial. By using
the SNPs provided herein to target a therapeutic agent to
individuals who are more likely to positively respond to the agent,
the therapeutic agent is more likely to succeed in clinical trials
by showing positive efficacy and to therefore satisfy the FDA
requirements for approval. Additionally, individuals who are more
likely to experience toxic or other undesirable side effects may be
excluded from being administered the therapeutic agent.
Furthermore, by using the SNPs provided herein to determine an
effective dosage or dosing frequency, for example, the therapeutic
agent may be less likely to exhibit toxicity or other undesirable
side effects, as well as more likely to achieve positive
efficacy.
[0163] Reports, Programmed Computers, Business Methods, and
Systems
[0164] The results of a test (e.g., an individual's risk for
psoriasis, Crohn's disease, or other autoinflammatory disease), or
an individual's predicted drug responsiveness (e.g., response to an
anti-IL12 or anti-IL23 therapy), based on assaying one or more SNPs
disclosed herein, and/or an individual's allele(s)/genotype at one
or more SNPs disclosed herein, etc.), and/or any other information
pertaining to a test, may be referred to herein as a "report". A
tangible report can optionally be generated as part of a testing
process (which may be interchangeably referred to herein as
"reporting", or as "providing" a report, "producing" a report, or
"generating" a report).
[0165] Examples of tangible reports may include, but are not
limited to, reports in paper (such as computer-generated printouts
of test results) or equivalent formats and reports stored on
computer readable medium (such as a CD, USB flash drive or other
removable storage device, computer hard drive, or computer network
server, etc.). Reports, particularly those stored on computer
readable medium, can be part of a database, which may optionally be
accessible via the internet (such as a database of patient records
or genetic information stored on a computer network server, which
may be a "secure database" that has security features that limit
access to the report, such as to allow only the patient and the
patient's medical practioners to view the report while preventing
other unauthorized individuals from viewing the report, for
example). In addition to, or as an alternative to, generating a
tangible report, reports can also be displayed on a computer screen
(or the display of another electronic device or instrument).
[0166] A report can include, for example, an individual's risk for
psoriasis, Crohn's disease, or other autoinflammatory disease, or
may just include the allele(s)/genotype that an individual carries
at one or more SNPs disclosed herein, which may optionally be
linked to information regarding the significance of having the
allele(s)/genotype at the SNP (for example, a report on computer
readable medium such as a network server may include hyperlink(s)
to one or more journal publications or websites that describe the
medical/biological implications, such as increased or decreased
disease risk, for individuals having a certain allele/genotype at
the SNP). Thus, for example, the report can include disease risk or
other medical/biological significance (e.g., drug responsiveness,
etc.) as well as optionally also including the allele/genotype
information, or the report may just include allele/genotype
information without including disease risk or other
medical/biological significance (such that an individual viewing
the report can use the allele/genotype information to determine the
associated disease risk or other medical/biological significance
from a source outside of the report itself, such as from a medical
practioner, publication, website, etc., which may optionally be
linked to the report such as by a hyperlink).
[0167] A report can further be "transmitted" or "communicated"
(these terms may be used herein interchangeably), such as to the
individual who was tested, a medical practitioner (e.g., a doctor,
nurse, clinical laboratory practitioner, genetic counselor, etc.),
a healthcare organization, a clinical laboratory, and/or any other
party or requester intended to view or possess the report. The act
of "transmitting" or "communicating" a report can be by any means
known in the art, based on the format of the report. Furthermore,
"transmitting" or "communicating" a report can include delivering a
report ("pushing") and/or retrieving ("pulling") a report. For
example, reports can be transmitted/communicated by various means,
including being physically transferred between parties (such as for
reports in paper format) such as by being physically delivered from
one party to another, or by being transmitted electronically or in
signal form (e.g., via e-mail or over the internet, by facsimile,
and/or by any wired or wireless communication methods known in the
art) such as by being retrieved from a database stored on a
computer network server, etc.
[0168] In certain exemplary embodiments, the invention provides
computers (or other apparatus/devices such as biomedical devices or
laboratory instrumentation) programmed to carry out the methods
described herein. For example, in certain embodiments, the
invention provides a computer programmed to receive (i.e., as
input) the identity (e.g., the allele(s) or genotype at a SNP) of
one or more SNPs disclosed herein and provide (i.e., as output) the
disease risk (e.g., an individual's risk for psoriasis, Crohn's
disease, or other autoinflammatory disease) or other result (e.g.,
disease diagnosis or prognosis, drug responsiveness, etc.) based on
the identity of the SNP(s). Such output (e.g., communication of
disease risk, disease diagnosis or prognosis, drug responsiveness,
etc.) may be, for example, in the form of a report on computer
readable medium, printed in paper form, and/or displayed on a
computer screen or other display.
[0169] In various exemplary embodiments, the invention further
provides methods of doing business (with respect to methods of
doing business, the terms "individual" and "customer" are used
herein interchangeably). For example, exemplary methods of doing
business can comprise assaying one or more SNPs disclosed herein
and providing a report that includes, for example, a customer's
risk for psoriasis, Crohn's disease, or other autoinflammatory
disease (based on which allele(s)/genotype is present at the
assayed SNP(s)) and/or that includes the allele(s)/genotype at the
assayed SNP(s) which may optionally be linked to information (e.g.,
journal publications, websites, etc.) pertaining to disease risk or
other biological/medical significance such as by means of a
hyperlink (the report may be provided, for example, on a computer
network server or other computer readable medium that is
internet-accessible, and the report may be included in a secure
database that allows the customer to access their report while
preventing other unauthorized individuals from viewing the report),
and optionally transmitting the report. Customers (or another party
who is associated with the customer, such as the customer's doctor,
for example) can request/order (e.g., purchase) the test online via
the internet (or by phone, mail order, at an outlet/store, etc.),
for example, and a kit can be sent/delivered (or otherwise
provided) to the customer (or another party on behalf of the
customer, such as the customer's doctor, for example) for
collection of a biological sample from the customer (e.g., a buccal
swab for collecting buccal cells), and the customer (or a party who
collects the customer's biological sample) can submit their
biological samples for assaying (e.g., to a laboratory or party
associated with the laboratory such as a party that accepts the
customer samples on behalf of the laboratory, a party for whom the
laboratory is under the control of (e.g., the laboratory carries
out the assays by request of the party or under a contract with the
party, for example), and/or a party that receives at least a
portion of the customer's payment for the test). The report (e.g.,
results of the assay including, for example, the customer's disease
risk and/or allele(s)/genotype at the assayed SNP(s)) may be
provided to the customer by, for example, the laboratory that
assays the SNP(s) or a party associated with the laboratory (e.g.,
a party that receives at least a portion of the customer's payment
for the assay, or a party that requests the laboratory to carry out
the assays or that contracts with the laboratory for the assays to
be carried out) or a doctor or other medical practitioner who is
associated with (e.g., employed by or having a consulting or
contracting arrangement with) the laboratory or with a party
associated with the laboratory, or the report may be provided to a
third party (e.g., a doctor, genetic counselor, hospital, etc.)
which optionally provides the report to the customer. In further
embodiments, the customer may be a doctor or other medical
practitioner, or a hospital, laboratory, medical insurance
organization, or other medical organization that requests/orders
(e.g., purchases) tests for the purposes of having other
individuals (e.g., their patients or customers) assayed for one or
more SNPs disclosed herein and optionally obtaining a report of the
assay results.
[0170] In certain exemplary methods of doing business, a kit for
collecting a biological sample (e.g., a buccal swab for collecting
buccal cells, or other sample collection device) is provided to a
medical practitioner (e.g., a physician) which the medical
practitioner uses to obtain a sample (e.g., buccal cells, saliva,
blood, etc.) from a patient, the sample is then sent to a
laboratory (e.g., a CLIA-certified laboratory) or other facility
that tests the sample for one or more SNPs disclosed herein (e.g.,
to determine the genotype of one or more SNPs disclosed herein,
such as to determine the patient's risk for psoriasis, Crohn's
disease, or other autoinflammatory disease), and the results of the
test (e.g., the patient's genotype at one or more SNPs disclosed
herein and/or the patient's disease risk based on their SNP
genotype) are provided back to the medical practitioner (and/or
directly to the patient and/or to another party such as a hospital,
medical insurance company, genetic counselor, etc.) who may then
provide or otherwise convey the results to the patient. The results
are typically provided in the form of a report, such as described
above.
[0171] In certain further exemplary methods of doing business, kits
for collecting a biological sample from a customer (e.g., a buccal
swab for collecting buccal cells, or other sample collection
device) are provided (e.g., for sale), such as at an outlet (e.g.,
a drug store, pharmacy, general merchandise store, or any other
desirable outlet), online via the internet, by mail order, etc.,
whereby customers can obtain (e.g., purchase) the kits, collect
their own biological samples, and submit (e.g., send/deliver via
mail) their samples to a laboratory (e.g., a CLIA-certified
laboratory) or other facility which tests the samples for one or
more SNPs disclosed herein (e.g., to determine the genotype of one
or more SNPs disclosed herein, such as to determine the customer's
risk for psoriasis, Crohn's disease, or other autoinflammatory
disease) and provides the results of the test (e.g., of the
customer's genotype at one or more SNPs disclosed herein and/or the
customer's disease risk based on their SNP genotype) back to the
customer and/or to a third party (e.g., a physician or other
medical practitioner, hospital, medical insurance company, genetic
counselor, etc.). The results are typically provided in the form of
a report, such as described above. If the results of the test are
provided to a third party, then this third party may optionally
provide another report to the customer based on the results of the
test (e.g., the result of the test from the laboratory may provide
the customer's genotype at one or more SNPs disclosed herein
without disease risk information, and the third party may provide a
report of the customer's disease risk based on this genotype
result).
[0172] Certain further embodiments of the invention provide a
system for determining an individual's autoinflammatory disease
risk (e.g., risk for psoriasis, Crohn's disease, etc.), or whether
an individual will benefit from anti-IL12 and/or anti-IL23
treatment (or other therapy) in reducing autoinflammatory disease
risk. Certain exemplary systems comprise an integrated "loop" in
which an individual (or their medical practitioner) requests a
determination of such individual's autoinflammatory disease risk
(or drug response, etc.), this determination is carried out by
testing a sample from the individual, and then the results of this
determination are provided back to the requestor. For example, in
certain systems, a sample (e.g., buccal cells, saliva, blood, etc.)
is obtained from an individual for testing (the sample may be
obtained by the individual or, for example, by a medical
practitioner), the sample is submitted to a laboratory (or other
facility) for testing (e.g., determining the genotype of one or
more SNPs disclosed herein), and then the results of the testing
are sent to the patient (which optionally can be done by first
sending the results to an intermediary, such as a medical
practioner, who then provides or otherwise conveys the results to
the individual and/or acts on the results), thereby forming an
integrated loop system for determining an individual's
autoinflammatory disease risk (or drug response, etc.). The
portions of the system in which the results are transmitted (e.g.,
between any of a testing facility, a medical practitioner, and/or
the individual) can be carried out by way of electronic or signal
transmission (e.g., by computer such as via e-mail or the internet,
by providing the results on a website or computer network server
which may optionally be a secure database, by phone or fax, or by
any other wired or wireless transmission methods known in the art).
Optionally, the system can further include a risk reduction
component (i.e., a disease management system) as part of the
integrated loop (for an example of a disease management system, see
U.S. Pat. No. 6,770,029, "Disease management system and method
including correlation assessment"). For example, the results of the
test can be used to reduce the risk of the disease in the
individual who was tested, such as by implementing a preventive
therapy regimen (e.g., administration of a drug regimen such as an
anti-IL12 and/or an anti-IL23 therapy for reducing autoinflammatory
disease risk), modifying the individual's diet, increasing
exercise, reducing stress, and/or implementing any other
physiological or behavioral modifications in the individual with
the goal of reducing disease risk. For reducing autoinflammatory
disease risk, this may include any means used in the art for
improving aspects of an individual's health relevant to reducing
autoinflammatory disease risk. Thus, in exemplary embodiments, the
system is controlled by the individual and/or their medical
practioner in that the individual and/or their medical practioner
requests the test, receives the test results back, and (optionally)
acts on the test results to reduce the individual's disease risk,
such as by implementing a disease management system.
[0173] The various methods described herein, such as correlating
the presence or absence of a polymorphism with an altered (e.g.,
increased or decreased) risk (or no altered risk) for psoriasis,
Crohn's disease, or other autoinflammatory disease (and/or
correlating the presence or absence of a polymorphism with the
predicted response of an individual to a drug such as an anti-IL12
and/or an anti-IL23 therapy), can be carried out by automated
methods such as by using a computer (or other apparatus/devices
such as biomedical devices, laboratory instrumentation, or other
apparatus/devices having a computer processor) programmed to carry
out any of the methods described herein. For example, computer
software (which may be interchangeably referred to herein as a
computer program) can perform the step of correlating the presence
or absence of a polymorphism in an individual with an altered
(e.g., increased or decreased) risk (or no altered risk) for
autoinflammatory disease (particularly risk for psoriasis or
Crohn's disease) for the individual. Computer software can also
perform the step of correlating the presence or absence of a
polymorphism in an individual with the predicted response of the
individual to a drug such as an anti-IL12 and/or an anti-IL23
therapy. Accordingly, certain embodiments of the invention provide
a computer (or other apparatus/device) programmed to carry out any
of the methods described herein.
[0174] Isolated Nucleic Acid Molecules and SNP Detection Reagents
& Kits
[0175] Tables 1 and 2 provide a variety of information about each
SNP of the present invention that is associated with psoriasis,
including the transcript sequences (SEQ ID NOS:1-2), genomic
sequences (SEQ ID NOS:13-20), and protein sequences (SEQ ID
NOS:3-4) of the encoded gene products (with the SNPs indicated by
IUB codes in the nucleic acid sequences). In addition, Tables 1 and
2 include SNP context sequences, which generally include 100
nucleotide upstream (5') plus 100 nucleotides downstream (3') of
each SNP position (SEQ ID NOS:5-12 correspond to transcript-based
SNP context sequences disclosed in Table 1, and SEQ ID NOS:21-307
correspond to genomic-based context sequences disclosed in Table
2), the alternative nucleotides (alleles) at each SNP position, and
additional information about the variant where relevant, such as
SNP type (coding, missense, splice site, UTR, etc.), human
populations in which the SNP was observed, observed allele
frequencies, information about the encoded protein, etc.
[0176] Isolated Nucleic Acid Molecules
[0177] The present invention provides isolated nucleic acid
molecules that contain one or more SNPs disclosed Table 1 and/or
Table 2. Isolated nucleic acid molecules containing one or more
SNPs disclosed in at least one of Tables 1 and 2 may be
interchangeably referred to throughout the present text as
"SNP-containing nucleic acid molecules." Isolated nucleic acid
molecules may optionally encode a full-length variant protein or
fragment thereof. The isolated nucleic acid molecules of the
present invention also include probes and primers (which are
described in greater detail below in the section entitled "SNP
Detection Reagents"), which may be used for assaying the disclosed
SNPs, and isolated full-length genes, transcripts, cDNA molecules,
and fragments thereof, which may be used for such purposes as
expressing an encoded protein.
[0178] As used herein, an "isolated nucleic acid molecule"
generally is one that contains a SNP of the present invention or
one that hybridizes to such molecule such as a nucleic acid with a
complementary sequence, and is separated from most other nucleic
acids present in the natural source of the nucleic acid molecule.
Moreover, an "isolated" nucleic acid molecule, such as a cDNA
molecule containing a SNP of the present invention, can be
substantially free of other cellular material, or culture medium
when produced by recombinant techniques, or chemical precursors or
other chemicals when chemically synthesized. A nucleic acid
molecule can be fused to other coding or regulatory sequences and
still be considered "isolated." Nucleic acid molecules present in
non-human transgenic animals, which do not naturally occur in the
animal, are also considered "isolated." For example, recombinant
DNA molecules contained in a vector are considered "isolated."
Further examples of "isolated" DNA molecules include recombinant
DNA molecules maintained in heterologous host cells, and purified
(partially or substantially) DNA molecules in solution. Isolated
RNA molecules include in vivo or in vitro RNA transcripts of the
isolated SNP-containing DNA molecules of the present invention.
Isolated nucleic acid molecules according to the present invention
further include such molecules produced synthetically.
[0179] Generally, an isolated SNP-containing nucleic acid molecule
comprises one or more SNP positions disclosed by the present
invention with flanking nucleotide sequences on either side of the
SNP positions. A flanking sequence can include nucleotide residues
that are naturally associated with the SNP site and/or heterologous
nucleotide sequences. Preferably, the flanking sequence is up to
about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4
nucleotides (or any other length in-between) on either side of a
SNP position, or as long as the full-length gene or entire
protein-coding sequence (or any portion thereof such as an exon),
especially if the SNP-containing nucleic acid molecule is to be
used to produce a protein or protein fragment.
[0180] For full-length genes and entire protein-coding sequences, a
SNP flanking sequence can be, for example, up to about 5 KB, 4 KB,
3 KB, 2 KB, 1 KB on either side of the SNP. Furthermore, in such
instances the isolated nucleic acid molecule comprises exonic
sequences (including protein-coding and/or non-coding exonic
sequences), but may also include intronic sequences. Thus, any
protein coding sequence may be either contiguous or separated by
introns. The important point is that the nucleic acid is isolated
from remote and unimportant flanking sequences and is of
appropriate length such that it can be subjected to the specific
manipulations or uses described herein such as recombinant protein
expression, preparation of probes and primers for assaying the SNP
position, and other uses specific to the SNP-containing nucleic
acid sequences.
[0181] An isolated SNP-containing nucleic acid molecule can
comprise, for example, a full-length gene or transcript, such as a
gene isolated from genomic DNA (e.g., by cloning or PCR
amplification), a cDNA molecule, or an mRNA transcript molecule.
Polymorphic transcript sequences are referred to in Table 1 and
provided in the Sequence Listing (SEQ ID NOS:1-2), and polymorphic
genomic sequences are referred to in Table 2 and provided in the
Sequence Listing (SEQ ID NOS:13-20). Furthermore, fragments of such
full-length genes and transcripts that contain one or more SNPs
disclosed herein are also encompassed by the present invention, and
such fragments may be used, for example, to express any part of a
protein, such as a particular functional domain or an antigenic
epitope.
[0182] Thus, the present invention also encompasses fragments of
the nucleic acid sequences as disclosed in Tables 1 and 2
(transcript sequences are referred to in Table 1 as SEQ ID NOS:1-2,
genomic sequences are referred to in Table 2 as SEQ ID NOS:13-20,
transcript-based SNP context sequences are referred to in Table 1
as SEQ ID NOS:5-12, and genomic-based SNP context sequences are
referred to in Table 2 as SEQ ID NOS:21-307) and their complements.
The actual sequences referred to in the tables are provided in the
Sequence Listing. A fragment typically comprises a contiguous
nucleotide sequence at least about 8 or more nucleotides, more
preferably at least about 12 or more nucleotides, and even more
preferably at least about 16 or more nucleotides. Furthermore, a
fragment could comprise at least about 18, 20, 22, 25, 30, 40, 50,
60, 80, 100, 150, 200, 250 or 500 nucleotides in length (or any
other number in between). The length of the fragment will be based
on its intended use. For example, the fragment can encode
epitope-bearing regions of a variant peptide or regions of a
variant peptide that differ from the normal/wild-type protein, or
can be useful as a polynucleotide probe or primer. Such fragments
can be isolated using the nucleotide sequences provided in Table 1
and/or Table 2 for the synthesis of a polynucleotide probe. A
labeled probe can then be used, for example, to screen a cDNA
library, genomic DNA library, or mRNA to isolate nucleic acid
corresponding to the coding region. Further, primers can be used in
amplification reactions, such as for purposes of assaying one or
more SNPs sites or for cloning specific regions of a gene.
[0183] An isolated nucleic acid molecule of the present invention
further encompasses a SNP-containing polynucleotide that is the
product of any one of a variety of nucleic acid amplification
methods, which are used to increase the copy numbers of a
polynucleotide of interest in a nucleic acid sample. Such
amplification methods are well known in the art, and they include
but are not limited to, polymerase chain reaction (PCR) (U.S. Pat.
Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and
Applications for DNA Amplification, ed. H. A. Erlich, Freeman
Press, NY, N.Y. (1992)), ligase chain reaction (LCR) (Wu and
Wallace, Genomics 4:560 (1989); Landegren et al., Science 241:1077
(1988)), strand displacement amplification (SDA) (U.S. Pat. Nos.
5,270,184 and 5,422,252), transcription-mediated amplification
(TMA) (U.S. Pat. No. 5,399,491), linked linear amplification (LLA)
(U.S. Pat. No. 6,027,923) and the like, and isothermal
amplification methods such as nucleic acid sequence based
amplification (NASBA) and self-sustained sequence replication
(Guatelli et al., Proc Natl Acad Sci USA 87:1874 (1990)). Based on
such methodologies, a person skilled in the art can readily design
primers in any suitable regions 5' and 3' to a SNP disclosed
herein. Such primers may be used to amplify DNA of any length so
long that it contains the SNP of interest in its sequence.
[0184] As used herein, an "amplified polynucleotide" of the
invention is a SNP-containing nucleic acid molecule whose amount
has been increased at least two fold by any nucleic acid
amplification method performed in vitro as compared to its starting
amount in a test sample. In other preferred embodiments, an
amplified polynucleotide is the result of at least ten fold, fifty
fold, one hundred fold, one thousand fold, or even ten thousand
fold increase as compared to its starting amount in a test sample.
In a typical PCR amplification, a polynucleotide of interest is
often amplified at least fifty thousand fold in amount over the
unamplified genomic DNA, but the precise amount of amplification
needed for an assay depends on the sensitivity of the subsequent
detection method used.
[0185] Generally, an amplified polynucleotide is at least about 16
nucleotides in length. More typically, an amplified polynucleotide
is at least about 20 nucleotides in length. In a preferred
embodiment of the invention, an amplified polynucleotide is at
least about 30 nucleotides in length. In a more preferred
embodiment of the invention, an amplified polynucleotide is at
least about 32, 40, 45, 50, or 60 nucleotides in length. In yet
another preferred embodiment of the invention, an amplified
polynucleotide is at least about 100, 200, 300, 400, or 500
nucleotides in length. While the total length of an amplified
polynucleotide of the invention can be as long as an exon, an
intron or the entire gene where the SNP of interest resides, an
amplified product is typically up to about 1,000 nucleotides in
length (although certain amplification methods may generate
amplified products greater than 1000 nucleotides in length). More
preferably, an amplified polynucleotide is not greater than about
600-700 nucleotides in length. It is understood that irrespective
of the length of an amplified polynucleotide, a SNP of interest may
be located anywhere along its sequence.
[0186] In a specific embodiment of the invention, the amplified
product is at least about 201 nucleotides in length, comprises one
of the transcript-based context sequences or the genomic-based
context sequences shown in Tables 1 and 2. Such a product may have
additional sequences on its 5' end or 3' end or both. In another
embodiment, the amplified product is about 101 nucleotides in
length, and it contains a SNP disclosed herein. Preferably, the SNP
is located at the middle of the amplified product (e.g., at
position 101 in an amplified product that is 201 nucleotides in
length, or at position 51 in an amplified product that is 101
nucleotides in length), or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 15, or 20 nucleotides from the middle of the amplified product.
However, as indicated above, the SNP of interest may be located
anywhere along the length of the amplified product.
[0187] The present invention provides isolated nucleic acid
molecules that comprise, consist of, or consist essentially of one
or more polynucleotide sequences that contain one or more SNPs
disclosed herein, complements thereof, and SNP-containing fragments
thereof.
[0188] Accordingly, the present invention provides nucleic acid
molecules that consist of any of the nucleotide sequences shown in
Table 1 and/or Table 2 (transcript sequences are referred to in
Table 1 as SEQ ID NOS:1-2, genomic sequences are referred to in
Table 2 as SEQ ID NOS:13-20, transcript-based SNP context sequences
are referred to in Table 1 as SEQ ID NOS:5-12, and genomic-based
SNP context sequences are referred to in Table 2 as SEQ ID
NOS:21-307), or any nucleic acid molecule that encodes any of the
variant proteins referred to in Table 1 (SEQ ID NOS:3-4). The
actual sequences referred to in the tables are provided in the
Sequence Listing. A nucleic acid molecule consists of a nucleotide
sequence when the nucleotide sequence is the complete nucleotide
sequence of the nucleic acid molecule.
[0189] The present invention further provides nucleic acid
molecules that consist essentially of any of the nucleotide
sequences referred to in Table 1 and/or Table 2 (transcript
sequences are referred to in Table 1 as SEQ ID NOS:1-2, genomic
sequences are referred to in Table 2 as SEQ ID NOS:13-20,
transcript-based SNP context sequences are referred to in Table 1
as SEQ ID NOS:5-12, and genomic-based SNP context sequences are
referred to in Table 2 as SEQ ID NOS:21-307), or any nucleic acid
molecule that encodes any of the variant proteins referred to in
Table 1 (SEQ ID NOS:3-4). The actual sequences referred to in the
tables are provided in the Sequence Listing. A nucleic acid
molecule consists essentially of a nucleotide sequence when such a
nucleotide sequence is present with only a few additional
nucleotide residues in the final nucleic acid molecule.
[0190] The present invention further provides nucleic acid
molecules that comprise any of the nucleotide sequences shown in
Table 1 and/or Table 2 or a SNP-containing fragment thereof
(transcript sequences are referred to in Table 1 as SEQ ID NOS:1-2,
genomic sequences are referred to in Table 2 as SEQ ID NOS:13-20,
transcript-based SNP context sequences are referred to in Table 1
as SEQ ID NOS:5-12, and genomic-based SNP context sequences are
referred to in Table 2 as SEQ ID NOS:21-307), or any nucleic acid
molecule that encodes any of the variant proteins provided in Table
1 (SEQ ID NOS:3-4). The actual sequences referred to in the tables
are provided in the Sequence Listing. A nucleic acid molecule
comprises a nucleotide sequence when the nucleotide sequence is at
least part of the final nucleotide sequence of the nucleic acid
molecule. In such a fashion, the nucleic acid molecule can be only
the nucleotide sequence or have additional nucleotide residues,
such as residues that are naturally associated with it or
heterologous nucleotide sequences. Such a nucleic acid molecule can
have one to a few additional nucleotides or can comprise many more
additional nucleotides. A brief description of how various types of
these nucleic acid molecules can be readily made and isolated is
provided below, and such techniques are well known to those of
ordinary skill in the art. Sambrook and Russell, Molecular Cloning:
A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).
[0191] The isolated nucleic acid molecules can encode mature
proteins plus additional amino or carboxyl-terminal amino acids or
both, or amino acids interior to the mature peptide (when the
mature form has more than one peptide chain, for instance). Such
sequences may play a role in processing of a protein from precursor
to a mature form, facilitate protein trafficking, prolong or
shorten protein half-life, or facilitate manipulation of a protein
for assay or production. As generally is the case in situ, the
additional amino acids may be processed away from the mature
protein by cellular enzymes.
[0192] Thus, the isolated nucleic acid molecules include, but are
not limited to, nucleic acid molecules having a sequence encoding a
peptide alone, a sequence encoding a mature peptide and additional
coding sequences such as a leader or secretory sequence (e.g., a
pre-pro or pro-protein sequence), a sequence encoding a mature
peptide with or without additional coding sequences, plus
additional non-coding sequences, for example introns and non-coding
5' and 3' sequences such as transcribed but untranslated sequences
that play a role in, for example, transcription, mRNA processing
(including splicing and polyadenylation signals), ribosome binding,
and/or stability of mRNA. In addition, the nucleic acid molecules
may be fused to heterologous marker sequences encoding, for
example, a peptide that facilitates purification.
[0193] Isolated nucleic acid molecules can be in the form of RNA,
such as mRNA, or in the form DNA, including cDNA and genomic DNA,
which may be obtained, for example, by molecular cloning or
produced by chemical synthetic techniques or by a combination
thereof. Sambrook and Russell, Molecular Cloning: A Laboratory
Manual, Cold Spring Harbor Press, N.Y. (2000). Furthermore,
isolated nucleic acid molecules, particularly SNP detection
reagents such as probes and primers, can also be partially or
completely in the form of one or more types of nucleic acid
analogs, such as peptide nucleic acid (PNA). U.S. Pat. Nos.
5,539,082; 5,527,675; 5,623,049; and 5,714,331. The nucleic acid,
especially DNA, can be double-stranded or single-stranded.
Single-stranded nucleic acid can be the coding strand (sense
strand) or the complementary non-coding strand (anti-sense strand).
DNA, RNA, or PNA segments can be assembled, for example, from
fragments of the human genome (in the case of DNA or RNA) or single
nucleotides, short oligonucleotide linkers, or from a series of
oligonucleotides, to provide a synthetic nucleic acid molecule.
Nucleic acid molecules can be readily synthesized using the
sequences provided herein as a reference; oligonucleotide and PNA
oligomer synthesis techniques are well known in the art. See, e.g.,
Corey, "Peptide nucleic acids: expanding the scope of nucleic acid
recognition," Trends Biotechnol 15(6):224-9 (June 1997), and Hyrup
et al., "Peptide nucleic acids (PNA): synthesis, properties and
potential applications," Bioorg Med Chem 4(1):5-23) (January 1996).
Furthermore, large-scale automated oligonucleotide/PNA synthesis
(including synthesis on an array or bead surface or other solid
support) can readily be accomplished using commercially available
nucleic acid synthesizers, such as the Applied Biosystems (Foster
City, Calif.) 3900 High-Throughput DNA Synthesizer or Expedite 8909
Nucleic Acid Synthesis System, and the sequence information
provided herein.
[0194] The present invention encompasses nucleic acid analogs that
contain modified, synthetic, or non-naturally occurring nucleotides
or structural elements or other alternative/modified nucleic acid
chemistries known in the art. Such nucleic acid analogs are useful,
for example, as detection reagents (e.g., primers/probes) for
detecting one or more SNPs identified in Table 1 and/or Table 2.
Furthermore, kits/systems (such as beads, arrays, etc.) that
include these analogs are also encompassed by the present
invention. For example, PNA oligomers that are based on the
polymorphic sequences of the present invention are specifically
contemplated. PNA oligomers are analogs of DNA in which the
phosphate backbone is replaced with a peptide-like backbone.
Lagriffoul et al., Bioorganic & Medicinal Chemistry Letters
4:1081-1082 (1994); Petersen et al., Bioorganic & Medicinal
Chemistry Letters 6:793-796 (1996); Kumar et al., Organic Letters
3(9):1269-1272 (2001); WO 96/04000. PNA hybridizes to complementary
RNA or DNA with higher affinity and specificity than conventional
oligonucleotides and oligonucleotide analogs. The properties of PNA
enable novel molecular biology and biochemistry applications
unachievable with traditional oligonucleotides and peptides.
[0195] Additional examples of nucleic acid modifications that
improve the binding properties and/or stability of a nucleic acid
include the use of base analogs such as inosine, intercalators
(U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat.
No. 5,801,115). Thus, references herein to nucleic acid molecules,
SNP-containing nucleic acid molecules, SNP detection reagents
(e.g., probes and primers), oligonucleotides/polynucleotides
include PNA oligomers and other nucleic acid analogs. Other
examples of nucleic acid analogs and alternative/modified nucleic
acid chemistries known in the art are described in Current
Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y.
(2002).
[0196] The present invention further provides nucleic acid
molecules that encode fragments of the variant polypeptides
disclosed herein as well as nucleic acid molecules that encode
obvious variants of such variant polypeptides. Such nucleic acid
molecules may be naturally occurring, such as paralogs (different
locus) and orthologs (different organism), or may be constructed by
recombinant DNA methods or by chemical synthesis. Non-naturally
occurring variants may be made by mutagenesis techniques, including
those applied to nucleic acid molecules, cells, or organisms.
Accordingly, the variants can contain nucleotide substitutions,
deletions, inversions and insertions (in addition to the SNPs
disclosed in Tables 1 and 2). Variation can occur in either or both
the coding and non-coding regions. The variations can produce
conservative and/or non-conservative amino acid substitutions.
[0197] Further variants of the nucleic acid molecules disclosed in
Tables 1 and 2, such as naturally occurring allelic variants (as
well as orthologs and paralogs) and synthetic variants produced by
mutagenesis techniques, can be identified and/or produced using
methods well known in the art. Such further variants can comprise a
nucleotide sequence that shares at least 70-80%, 80-85%, 85-90%,
91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity
with a nucleic acid sequence disclosed in Table 1 and/or Table 2
(or a fragment thereof) and that includes a novel SNP allele
disclosed in Table 1 and/or Table 2. Further, variants can comprise
a nucleotide sequence that encodes a polypeptide that shares at
least 70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,
98%, or 99% sequence identity with a polypeptide sequence disclosed
in Table 1 (or a fragment thereof) and that includes a novel SNP
allele disclosed in Table 1 and/or Table 2. Thus, an aspect of the
present invention that is specifically contemplated are isolated
nucleic acid molecules that have a certain degree of sequence
variation compared with the sequences shown in Tables 1-2, but that
contain a novel SNP allele disclosed herein. In other words, as
long as an isolated nucleic acid molecule contains a novel SNP
allele disclosed herein, other portions of the nucleic acid
molecule that flank the novel SNP allele can vary to some degree
from the specific transcript, genomic, and context sequences
referred to and shown in Tables 1 and 2, and can encode a
polypeptide that varies to some degree from the specific
polypeptide sequences referred to in Table 1.
[0198] To determine the percent identity of two amino acid
sequences or two nucleotide sequences of two molecules that share
sequence homology, the sequences are aligned for optimal comparison
purposes (e.g., gaps can be introduced in one or both of a first
and a second amino acid or nucleic acid sequence for optimal
alignment and non-homologous sequences can be disregarded for
comparison purposes). In a preferred embodiment, at least 30%, 40%,
50%, 60%, 70%, 80%, or 90% or more of the length of a reference
sequence is aligned for comparison purposes. The amino acid
residues or nucleotides at corresponding amino acid positions or
nucleotide positions are then compared. When a position in the
first sequence is occupied by the same amino acid residue or
nucleotide as the corresponding position in the second sequence,
then the molecules are identical at that position (as used herein,
amino acid or nucleic acid "identity" is equivalent to amino acid
or nucleic acid "homology"). The percent identity between the two
sequences is a function of the number of identical positions shared
by the sequences, taking into account the number of gaps, and the
length of each gap, which need to be introduced for optimal
alignment of the two sequences.
[0199] The comparison of sequences and determination of percent
identity between two sequences can be accomplished using a
mathematical algorithm. Computational Molecular Biology, A. M.
Lesk, ed., Oxford University Press, N.Y (1988); Biocomputing:
Informatics and Genome Projects, D. W. Smith, ed., Academic Press,
N.Y. (1993); Computer Analysis of Sequence Data, Part 1, A. M.
Griffin and H. G. Griffin, eds., Humana Press, N.J. (1994);
Sequence Analysis in Molecular Biology, G. von Heinje, ed.,
Academic Press, N.Y. (1987); and Sequence Analysis Primer, M.
Gribskov and J. Devereux, eds., M. Stockton Press, N.Y. (1991). In
a preferred embodiment, the percent identity between two amino acid
sequences is determined using the Needleman and Wunsch algorithm (J
Mol Biol (48):444-453 (1970)) which has been incorporated into the
GAP program in the GCG software package, using either a Blossom 62
matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8,
6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
[0200] In yet another preferred embodiment, the percent identity
between two nucleotide sequences is determined using the GAP
program in the GCG software package using a NWSgapdna.CMP matrix
and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1,
2, 3, 4, 5, or 6. J. Devereux et al., Nucleic Acids Res. 12(1):387
(1984). In another embodiment, the percent identity between two
amino acid or nucleotide sequences is determined using the
algorithm of E. Myers and W. Miller (CABIOS 4:11-17 (1989)) which
has been incorporated into the ALIGN program (version 2.0), using a
PAM120 weight residue table, a gap length penalty of 12, and a gap
penalty of 4.
[0201] The nucleotide and amino acid sequences of the present
invention can further be used as a "query sequence" to perform a
search against sequence databases; for example, to identify other
family members or related sequences. Such searches can be performed
using the NBLAST and XBLAST programs (version 2.0). Altschul et
al., J Mol Biol 215:403-10 (1990). BLAST nucleotide searches can be
performed with the NBLAST program, score=100, wordlength=12 to
obtain nucleotide sequences homologous to the nucleic acid
molecules of the invention. BLAST protein searches can be performed
with the XBLAST program, score=50, wordlength=3 to obtain amino
acid sequences homologous to the proteins of the invention. To
obtain gapped alignments for comparison purposes, Gapped BLAST can
be utilized. Altschul et al., Nucleic Acids Res 25(17):3389-3402
(1997). When utilizing BLAST and gapped BLAST programs, the default
parameters of the respective programs (e.g., XBLAST and NBLAST) can
be used. In addition to BLAST, examples of other search and
sequence comparison programs used in the art include, but are not
limited to, FASTA (Pearson, Methods Mol Biol 25, 365-389 (1994))
and KERR (Dufresne et al., Nat Biotechnol 20(12):1269-71 (December
2002)). For further information regarding bioinformatics
techniques, see Current Protocols in Bioinformatics, John Wiley
& Sons, Inc., N.Y.
[0202] The present invention further provides non-coding fragments
of the nucleic acid molecules disclosed in Table 1 and/or Table 2.
Preferred non-coding fragments include, but are not limited to,
promoter sequences, enhancer sequences, intronic sequences, 5'
untranslated regions (UTRs), 3' untranslated regions, gene
modulating sequences and gene termination sequences. Such fragments
are useful, for example, in controlling heterologous gene
expression and in developing screens to identify gene-modulating
agents.
[0203] SNP Detection Reagents
[0204] In a specific aspect of the present invention, the SNPs
disclosed in Table 1 and/or Table 2, and their associated
transcript sequences (referred to in Table 1 as SEQ ID NOS:1-2),
genomic sequences (referred to in Table 2 as SEQ ID NOS:13-20), and
context sequences (transcript-based context sequences are referred
to in Table 1 as SEQ ID NOS:5-12; genomic-based context sequences
are provided in Table 2 as SEQ ID NOS:21-307), can be used for the
design of SNP detection reagents. The actual sequences referred to
in the tables are provided in the Sequence Listing. As used herein,
a "SNP detection reagent" is a reagent that specifically detects a
specific target SNP position disclosed herein, and that is
preferably specific for a particular nucleotide (allele) of the
target SNP position (i.e., the detection reagent preferably can
differentiate between different alternative nucleotides at a target
SNP position, thereby allowing the identity of the nucleotide
present at the target SNP position to be determined). Typically,
such detection reagent hybridizes to a target SNP-containing
nucleic acid molecule by complementary base-pairing in a sequence
specific manner, and discriminates the target variant sequence from
other nucleic acid sequences such as an art-known form in a test
sample. An example of a detection reagent is a probe that
hybridizes to a target nucleic acid containing one or more of the
SNPs referred to in Table 1 and/or Table 2. In a preferred
embodiment, such a probe can differentiate between nucleic acids
having a particular nucleotide (allele) at a target SNP position
from other nucleic acids that have a different nucleotide at the
same target SNP position. In addition, a detection reagent may
hybridize to a specific region 5' and/or 3' to a SNP position,
particularly a region corresponding to the context sequences
referred to in Table 1 and/or Table 2 (transcript-based context
sequences are referred to in Table 1 as SEQ ID NOS:5-12;
genomic-based context sequences are referred to in Table 2 as SEQ
ID NOS:21-307). Another example of a detection reagent is a primer
that acts as an initiation point of nucleotide extension along a
complementary strand of a target polynucleotide. The SNP sequence
information provided herein is also useful for designing primers,
e.g. allele-specific primers, to amplify (e.g., using PCR) any SNP
of the present invention.
[0205] In one preferred embodiment of the invention, a SNP
detection reagent is an isolated or synthetic DNA or RNA
polynucleotide probe or primer or PNA oligomer, or a combination of
DNA, RNA and/or PNA, that hybridizes to a segment of a target
nucleic acid molecule containing a SNP identified in Table 1 and/or
Table 2. A detection reagent in the form of a polynucleotide may
optionally contain modified base analogs, intercalators or minor
groove binders. Multiple detection reagents such as probes may be,
for example, affixed to a solid support (e.g., arrays or beads) or
supplied in solution (e.g. probe/primer sets for enzymatic
reactions such as PCR, RT-PCR, TaqMan assays, or primer-extension
reactions) to form a SNP detection kit.
[0206] A probe or primer typically is a substantially purified
oligonucleotide or PNA oligomer. Such oligonucleotide typically
comprises a region of complementary nucleotide sequence that
hybridizes under stringent conditions to at least about 8, 10, 12,
16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120
(or any other number in-between) or more consecutive nucleotides in
a target nucleic acid molecule. Depending on the particular assay,
the consecutive nucleotides can either include the target SNP
position, or be a specific region in close enough proximity 5'
and/or 3' to the SNP position to carry out the desired assay.
[0207] Other preferred primer and probe sequences can readily be
determined using the transcript sequences (SEQ ID NOS:1-2), genomic
sequences (SEQ ID NOS:13-20), and SNP context sequences
(transcript-based context sequences are referred to in Table 1 as
SEQ ID NOS:5-12; genomic-based context sequences are referred to in
Table 2 as SEQ ID NOS:21-307) disclosed in the Sequence Listing and
in Tables 1 and 2. The actual sequences referred to in the tables
are provided in the Sequence Listing. It will be apparent to one of
skill in the art that such primers and probes are directly useful
as reagents for genotyping the SNPs of the present invention, and
can be incorporated into any kit/system format.
[0208] In order to produce a probe or primer specific for a target
SNP-containing sequence, the gene/transcript and/or context
sequence surrounding the SNP of interest is typically examined
using a computer algorithm that starts at the 5' or at the 3' end
of the nucleotide sequence. Typical algorithms will then identify
oligomers of defined length that are unique to the gene/SNP context
sequence, have a GC content within a range suitable for
hybridization, lack predicted secondary structure that may
interfere with hybridization, and/or possess other desired
characteristics or that lack other undesired characteristics.
[0209] A primer or probe of the present invention is typically at
least about 8 nucleotides in length. In one embodiment of the
invention, a primer or a probe is at least about 10 nucleotides in
length. In a preferred embodiment, a primer or a probe is at least
about 12 nucleotides in length. In a more preferred embodiment, a
primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23,
24 or 25 nucleotides in length. While the maximal length of a probe
can be as long as the target sequence to be detected, depending on
the type of assay in which it is employed, it is typically less
than about 50, 60, 65, or 70 nucleotides in length. In the case of
a primer, it is typically less than about 30 nucleotides in length.
In a specific preferred embodiment of the invention, a primer or a
probe is within the length of about 18 and about 28 nucleotides.
However, in other embodiments, such as nucleic acid arrays and
other embodiments in which probes are affixed to a substrate, the
probes can be longer, such as on the order of 30-70, 75, 80, 90,
100, or more nucleotides in length (see the section below entitled
"SNP Detection Kits and Systems").
[0210] For analyzing SNPs, it may be appropriate to use
oligonucleotides specific for alternative SNP alleles. Such
oligonucleotides that detect single nucleotide variations in target
sequences may be referred to by such terms as "allele-specific
oligonucleotides," "allele-specific probes," or "allele-specific
primers." The design and use of allele-specific probes for
analyzing polymorphisms is described in, e.g., Mutation Detection:
A Practical Approach, Cotton et al., eds., Oxford University Press
(1998); Saiki et al., Nature 324:163-166 (1986); Dattagupta,
EP235,726; and Saiki, WO 89/11548.
[0211] While the design of each allele-specific primer or probe
depends on variables such as the precise composition of the
nucleotide sequences flanking a SNP position in a target nucleic
acid molecule, and the length of the primer or probe, another
factor in the use of primers and probes is the stringency of the
condition under which the hybridization between the probe or primer
and the target sequence is performed. Higher stringency conditions
utilize buffers with lower ionic strength and/or a higher reaction
temperature, and tend to require a more perfect match between
probe/primer and a target sequence in order to form a stable
duplex. If the stringency is too high, however, hybridization may
not occur at all. In contrast, lower stringency conditions utilize
buffers with higher ionic strength and/or a lower reaction
temperature, and permit the formation of stable duplexes with more
mismatched bases between a probe/primer and a target sequence. By
way of example and not limitation, exemplary conditions for high
stringency hybridization conditions using an allele-specific probe
are as follows: prehybridization with a solution containing
5.times. standard saline phosphate EDTA (SSPE), 0.5% NaDodSO.sub.4
(SDS) at 55.degree. C., and incubating probe with target nucleic
acid molecules in the same solution at the same temperature,
followed by washing with a solution containing 2.times.SSPE, and
0.1% SDS at 55.degree. C. or room temperature.
[0212] Moderate stringency hybridization conditions may be used for
allele-specific primer extension reactions with a solution
containing, e.g., about 50 mM KCl at about 46.degree. C.
Alternatively, the reaction may be carried out at an elevated
temperature such as 60.degree. C. In another embodiment, a
moderately stringent hybridization condition suitable for
oligonucleotide ligation assay (OLA) reactions wherein two probes
are ligated if they are completely complementary to the target
sequence may utilize a solution of about 100 mM KCl at a
temperature of 46.degree. C.
[0213] In a hybridization-based assay, allele-specific probes can
be designed that hybridize to a segment of target DNA from one
individual but do not hybridize to the corresponding segment from
another individual due to the presence of different polymorphic
forms (e.g., alternative SNP alleles/nucleotides) in the respective
DNA segments from the two individuals. Hybridization conditions
should be sufficiently stringent that there is a significant
detectable difference in hybridization intensity between alleles,
and preferably an essentially binary response, whereby a probe
hybridizes to only one of the alleles or significantly more
strongly to one allele. While a probe may be designed to hybridize
to a target sequence that contains a SNP site such that the SNP
site aligns anywhere along the sequence of the probe, the probe is
preferably designed to hybridize to a segment of the target
sequence such that the SNP site aligns with a central position of
the probe (e.g., a position within the probe that is at least three
nucleotides from either end of the probe). This design of probe
generally achieves good discrimination in hybridization between
different allelic forms.
[0214] In another embodiment, a probe or primer may be designed to
hybridize to a segment of target DNA such that the SNP aligns with
either the 5' most end or the 3' most end of the probe or primer.
In a specific preferred embodiment that is particularly suitable
for use in a oligonucleotide ligation assay (U.S. Pat. No.
4,988,617), the 3'most nucleotide of the probe aligns with the SNP
position in the target sequence.
[0215] Oligonucleotide probes and primers may be prepared by
methods well known in the art. Chemical synthetic methods include,
but are not limited to, the phosphotriester method described by
Narang et al., Methods in Enzymology 68:90 (1979); the
phosphodiester method described by Brown et al., Methods in
Enzymology 68:109 (1979); the diethylphosphoamidate method
described by Beaucage et al., Tetrahedron Letters 22:1859 (1981);
and the solid support method described in U.S. Pat. No.
4,458,066.
[0216] Allele-specific probes are often used in pairs (or, less
commonly, in sets of 3 or 4, such as if a SNP position is known to
have 3 or 4 alleles, respectively, or to assay both strands of a
nucleic acid molecule for a target SNP allele), and such pairs may
be identical except for a one nucleotide mismatch that represents
the allelic variants at the SNP position. Commonly, one member of a
pair perfectly matches a reference form of a target sequence that
has a more common SNP allele (i.e., the allele that is more
frequent in the target population) and the other member of the pair
perfectly matches a form of the target sequence that has a less
common SNP allele (i.e., the allele that is rarer in the target
population). In the case of an array, multiple pairs of probes can
be immobilized on the same support for simultaneous analysis of
multiple different polymorphisms.
[0217] In one type of PCR-based assay, an allele-specific primer
hybridizes to a region on a target nucleic acid molecule that
overlaps a SNP position and only primes amplification of an allelic
form to which the primer exhibits perfect complementarity. Gibbs,
Nucleic Acid Res 17:2427-2448 (1989). Typically, the primer's
3'-most nucleotide is aligned with and complementary to the SNP
position of the target nucleic acid molecule. This primer is used
in conjunction with a second primer that hybridizes at a distal
site. Amplification proceeds from the two primers, producing a
detectable product that indicates which allelic form is present in
the test sample. A control is usually performed with a second pair
of primers, one of which shows a single base mismatch at the
polymorphic site and the other of which exhibits perfect
complementarity to a distal site. The single-base mismatch prevents
amplification or substantially reduces amplification efficiency, so
that either no detectable product is formed or it is formed in
lower amounts or at a slower pace. The method generally works most
effectively when the mismatch is at the 3'-most position of the
oligonucleotide (i.e., the 3'-most position of the oligonucleotide
aligns with the target SNP position) because this position is most
destabilizing to elongation from the primer (see, e.g., WO
93/22456). This PCR-based assay can be utilized as part of the
TaqMan assay, described below.
[0218] In a specific embodiment of the invention, a primer of the
invention contains a sequence substantially complementary to a
segment of a target SNP-containing nucleic acid molecule except
that the primer has a mismatched nucleotide in one of the three
nucleotide positions at the 3'-most end of the primer, such that
the mismatched nucleotide does not base pair with a particular
allele at the SNP site. In a preferred embodiment, the mismatched
nucleotide in the primer is the second from the last nucleotide at
the 3'-most position of the primer. In a more preferred embodiment,
the mismatched nucleotide in the primer is the last nucleotide at
the 3'-most position of the primer.
[0219] In another embodiment of the invention, a SNP detection
reagent of the invention is labeled with a fluorogenic reporter dye
that emits a detectable signal. While the preferred reporter dye is
a fluorescent dye, any reporter dye that can be attached to a
detection reagent such as an oligonucleotide probe or primer is
suitable for use in the invention. Such dyes include, but are not
limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5,
Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6-Fam, Tet,
Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and
Texas Red.
[0220] In yet another embodiment of the invention, the detection
reagent may be further labeled with a quencher dye such as Tamra,
especially when the reagent is used as a self-quenching probe such
as a TaqMan (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular
Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other
stemless or linear beacon probe (Livak et al., PCR Method Appl
4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308
(1996); Nazarenko et al., Nucl Acids Res 25:2516-2521 (1997); U.S.
Pat. Nos. 5,866,336 and 6,117,635.
[0221] The detection reagents of the invention may also contain
other labels, including but not limited to, biotin for streptavidin
binding, hapten for antibody binding, and oligonucleotide for
binding to another complementary oligonucleotide such as pairs of
zipcodes.
[0222] The present invention also contemplates reagents that do not
contain (or that are complementary to) a SNP nucleotide identified
herein but that are used to assay one or more SNPs disclosed
herein. For example, primers that flank, but do not hybridize
directly to a target SNP position provided herein are useful in
primer extension reactions in which the primers hybridize to a
region adjacent to the target SNP position (i.e., within one or
more nucleotides from the target SNP site). During the primer
extension reaction, a primer is typically not able to extend past a
target SNP site if a particular nucleotide (allele) is present at
that target SNP site, and the primer extension product can be
detected in order to determine which SNP allele is present at the
target SNP site. For example, particular ddNTPs are typically used
in the primer extension reaction to terminate primer extension once
a ddNTP is incorporated into the extension product (a primer
extension product which includes a ddNTP at the 3'-most end of the
primer extension product, and in which the ddNTP is a nucleotide of
a SNP disclosed herein, is a composition that is specifically
contemplated by the present invention). Thus, reagents that bind to
a nucleic acid molecule in a region adjacent to a SNP site and that
are used for assaying the SNP site, even though the bound sequences
do not necessarily include the SNP site itself, are also
contemplated by the present invention.
[0223] SNP Detection Kits and Systems
[0224] A person skilled in the art will recognize that, based on
the SNP and associated sequence information disclosed herein,
detection reagents can be developed and used to assay any SNP of
the present invention individually or in combination, and such
detection reagents can be readily incorporated into one of the
established kit or system formats which are well known in the art.
The terms "kits" and "systems," as used herein in the context of
SNP detection reagents, are intended to refer to such things as
combinations of multiple SNP detection reagents, or one or more SNP
detection reagents in combination with one or more other types of
elements or components (e.g., other types of biochemical reagents,
containers, packages such as packaging intended for commercial
sale, substrates to which SNP detection reagents are attached,
electronic hardware components, etc.). Accordingly, the present
invention further provides SNP detection kits and systems,
including but not limited to, packaged probe and primer sets (e.g.
TaqMan probe/primer sets), arrays/microarrays of nucleic acid
molecules, and beads that contain one or more probes, primers, or
other detection reagents for detecting one or more SNPs of the
present invention. The kits/systems can optionally include various
electronic hardware components; for example, arrays ("DNA chips")
and microfluidic systems ("lab-on-a-chip" systems) provided by
various manufacturers typically comprise hardware components. Other
kits/systems (e.g., probe/primer sets) may not include electronic
hardware components, but may be comprised of, for example, one or
more SNP detection reagents (along with, optionally, other
biochemical reagents) packaged in one or more containers.
[0225] In some embodiments, a SNP detection kit typically contains
one or more detection reagents and other components (e.g. a buffer,
enzymes such as DNA polymerases or ligases, chain extension
nucleotides such as deoxynucleotide triphosphates, and in the case
of Sanger-type DNA sequencing reactions, chain terminating
nucleotides, positive control sequences, negative control
sequences, and the like) necessary to carry out an assay or
reaction, such as amplification and/or detection of a
SNP-containing nucleic acid molecule. A kit may further contain
means for determining the amount of a target nucleic acid, and
means for comparing the amount with a standard, and can comprise
instructions for using the kit to detect the SNP-containing nucleic
acid molecule of interest. In one embodiment of the present
invention, kits are provided which contain the necessary reagents
to carry out one or more assays to detect one or more SNPs
disclosed herein. In a preferred embodiment of the present
invention, SNP detection kits/systems are in the form of nucleic
acid arrays, or compartmentalized kits, including
microfluidic/lab-on-a-chip systems.
[0226] SNP detection kits/systems may contain, for example, one or
more probes, or pairs of probes, that hybridize to a nucleic acid
molecule at or near each target SNP position. Multiple pairs of
allele-specific probes may be included in the kit/system to
simultaneously assay large numbers of SNPs, at least one of which
is a SNP of the present invention. In some kits/systems, the
allele-specific probes are immobilized to a substrate such as an
array or bead. For example, the same substrate can comprise
allele-specific probes for detecting at least 1; 10; 100; 1000;
10,000; 100,000 (or any other number in-between) or substantially
all of the SNPs shown in Table 1 and/or Table 2.
[0227] The terms "arrays," "microarrays," and "DNA chips" are used
herein interchangeably to refer to an array of distinct
polynucleotides affixed to a substrate, such as glass, plastic,
paper, nylon or other type of membrane, filter, chip, or any other
suitable solid support. The polynucleotides can be synthesized
directly on the substrate, or synthesized separate from the
substrate and then affixed to the substrate. In one embodiment, the
microarray is prepared and used according to the methods described
in Chee et al., U.S. Pat. No. 5,837,832 and PCT application
WO95/11995; D. J. Lockhart et al., Nat Biotech 14:1675-1680 (1996);
and M. Schena et al., Proc Natl Acad Sci 93:10614-10619 (1996), all
of which are incorporated herein in their entirety by reference. In
other embodiments, such arrays are produced by the methods
described by Brown et al., U.S. Pat. No. 5,807,522.
[0228] Nucleic acid arrays are reviewed in the following
references: Zammatteo et al., "New chips for molecular biology and
diagnostics," Biotechnol Annu Rev 8:85-101 (2002); Sosnowski et
al., "Active microelectronic array system for DNA hybridization,
genotyping and pharmacogenomic applications," Psychiatr Genet
12(4):181-92 (December 2002); Heller, "DNA microarray technology:
devices, systems, and applications," Annu Rev Biomed Eng 4:129-53
(2002); Epub Mar. 22, 2002; Kolchinsky et al., "Analysis of SNPs
and other genomic variations using gel-based chips," Hum Mutat
19(4):343-60 (April 2002); and McGall et al., "High-density
genechip oligonucleotide probe arrays," Adv Biochem Eng Biotechnol
77:21-42 (2002).
[0229] Any number of probes, such as allele-specific probes, may be
implemented in an array, and each probe or pair of probes can
hybridize to a different SNP position. In the case of
polynucleotide probes, they can be synthesized at designated areas
(or synthesized separately and then affixed to designated areas) on
a substrate using a light-directed chemical process. Each DNA chip
can contain, for example, thousands to millions of individual
synthetic polynucleotide probes arranged in a grid-like pattern and
miniaturized (e.g., to the size of a dime). Preferably, probes are
attached to a solid support in an ordered, addressable array.
[0230] A microarray can be composed of a large number of unique,
single-stranded polynucleotides, usually either synthetic antisense
polynucleotides or fragments of cDNAs, fixed to a solid support.
Typical polynucleotides are preferably about 6-60 nucleotides in
length, more preferably about 15-30 nucleotides in length, and most
preferably about 18-25 nucleotides in length. For certain types of
microarrays or other detection kits/systems, it may be preferable
to use oligonucleotides that are only about 7-20 nucleotides in
length. In other types of arrays, such as arrays used in
conjunction with chemiluminescent detection technology, preferred
probe lengths can be, for example, about 15-80 nucleotides in
length, preferably about 50-70 nucleotides in length, more
preferably about 55-65 nucleotides in length, and most preferably
about 60 nucleotides in length. The microarray or detection kit can
contain polynucleotides that cover the known 5' or 3' sequence of a
gene/transcript or target SNP site, sequential polynucleotides that
cover the full-length sequence of a gene/transcript; or unique
polynucleotides selected from particular areas along the length of
a target gene/transcript sequence, particularly areas corresponding
to one or more SNPs disclosed in Table 1 and/or Table 2.
Polynucleotides used in the microarray or detection kit can be
specific to a SNP or SNPs of interest (e.g., specific to a
particular SNP allele at a target SNP site, or specific to
particular SNP alleles at multiple different SNP sites), or
specific to a polymorphic gene/transcript or genes/transcripts of
interest.
[0231] Hybridization assays based on polynucleotide arrays rely on
the differences in hybridization stability of the probes to
perfectly matched and mismatched target sequence variants. For SNP
genotyping, it is generally preferable that stringency conditions
used in hybridization assays are high enough such that nucleic acid
molecules that differ from one another at as little as a single SNP
position can be differentiated (e.g., typical SNP hybridization
assays are designed so that hybridization will occur only if one
particular nucleotide is present at a SNP position, but will not
occur if an alternative nucleotide is present at that SNP
position). Such high stringency conditions may be preferable when
using, for example, nucleic acid arrays of allele-specific probes
for SNP detection. Such high stringency conditions are described in
the preceding section, and are well known to those skilled in the
art and can be found in, for example, Current Protocols in
Molecular Biology 6.3.1-6.3.6, John Wiley & Sons, N.Y.
(1989).
[0232] In other embodiments, the arrays are used in conjunction
with chemiluminescent detection technology. The following patents
and patent applications, which are all hereby incorporated by
reference, provide additional information pertaining to
chemiluminescent detection. U.S. patent applications that describe
chemiluminescent approaches for microarray detection: Ser. Nos.
10/620,332 and 10/620,333. U.S. patents that describe methods and
compositions of dioxetane for performing chemiluminescent
detection: U.S. Pat. Nos. 6,124,478; 6,107,024; 5,994,073;
5,981,768; 5,871,938; 5,843,681; 5,800,999 and 5,773,628. And the
U.S. published application that discloses methods and compositions
for microarray controls: US2002/0110828.
[0233] In one embodiment of the invention, a nucleic acid array can
comprise an array of probes of about 15-25 nucleotides in length.
In further embodiments, a nucleic acid array can comprise any
number of probes, in which at least one probe is capable of
detecting one or more SNPs disclosed in Table 1 and/or Table 2,
and/or at least one probe comprises a fragment of one of the
sequences selected from the group consisting of those disclosed in
Table 1, Table 2, the Sequence Listing, and sequences complementary
thereto, said fragment comprising at least about 8 consecutive
nucleotides, preferably 10, 12, 15, 16, 18, 20, more preferably 22,
25, 30, 40, 47, 50, 55, 60, 65, 70, 80, 90, 100, or more
consecutive nucleotides (or any other number in-between) and
containing (or being complementary to) a novel SNP allele disclosed
in Table 1 and/or Table 2. In some embodiments, the nucleotide
complementary to the SNP site is within 5, 4, 3, 2, or 1 nucleotide
from the center of the probe, more preferably at the center of said
probe.
[0234] A polynucleotide probe can be synthesized on the surface of
the substrate by using a chemical coupling procedure and an ink jet
application apparatus, as described in PCT application WO95/251116
(Baldeschweiler et al.) which is incorporated herein in its
entirety by reference. In another aspect, a "gridded" array
analogous to a dot (or slot) blot may be used to arrange and link
cDNA fragments or oligonucleotides to the surface of a substrate
using a vacuum system, thermal, UV, mechanical or chemical bonding
procedures. An array, such as those described above, may be
produced by hand or by using available devices (slot blot or dot
blot apparatus), materials (any suitable solid support), and
machines (including robotic instruments), and may contain 8, 24,
96, 384, 1536, 6144 or more polynucleotides, or any other number
which lends itself to the efficient use of commercially available
instrumentation.
[0235] Using such arrays or other kits/systems, the present
invention provides methods of identifying the SNPs disclosed herein
in a test sample. Such methods typically involve incubating a test
sample of nucleic acids with an array comprising one or more probes
corresponding to at least one SNP position of the present
invention, and assaying for binding of a nucleic acid from the test
sample with one or more of the probes. Conditions for incubating a
SNP detection reagent (or a kit/system that employs one or more
such SNP detection reagents) with a test sample vary. Incubation
conditions depend on such factors as the format employed in the
assay, the detection methods employed, and the type and nature of
the detection reagents used in the assay. One skilled in the art
will recognize that any one of the commonly available
hybridization, amplification and array assay formats can readily be
adapted to detect the SNPs disclosed herein.
[0236] A SNP detection kit/system of the present invention may
include components that are used to prepare nucleic acids from a
test sample for the subsequent amplification and/or detection of a
SNP-containing nucleic acid molecule. Such sample preparation
components can be used to produce nucleic acid extracts (including
DNA and/or RNA), proteins or membrane extracts from any bodily
fluids (such as blood, serum, plasma, urine, saliva, phlegm,
gastric juices, semen, tears, sweat, etc.), skin, hair, cells
(especially nucleated cells), biopsies, buccal swabs or tissue
specimens. The test samples used in the above-described methods
will vary based on such factors as the assay format, nature of the
detection method, and the specific tissues, cells or extracts used
as the test sample to be assayed. Methods of preparing nucleic
acids, proteins, and cell extracts are well known in the art and
can be readily adapted to obtain a sample that is compatible with
the system utilized. Automated sample preparation systems for
extracting nucleic acids from a test sample are commercially
available, and examples are Qiagen's BioRobot 9600, Applied
Biosystems' PRISM.TM. 6700 sample preparation system, and Roche
Molecular Systems' COBAS AmpliPrep System.
[0237] Another form of kit contemplated by the present invention is
a compartmentalized kit. A compartmentalized kit includes any kit
in which reagents are contained in separate containers. Such
containers include, for example, small glass containers, plastic
containers, strips of plastic, glass or paper, or arraying material
such as silica. Such containers allow one to efficiently transfer
reagents from one compartment to another compartment such that the
test samples and reagents are not cross-contaminated, or from one
container to another vessel not included in the kit, and the agents
or solutions of each container can be added in a quantitative
fashion from one compartment to another or to another vessel. Such
containers may include, for example, one or more containers which
will accept the test sample, one or more containers which contain
at least one probe or other SNP detection reagent for detecting one
or more SNPs of the present invention, one or more containers which
contain wash reagents (such as phosphate buffered saline,
Tris-buffers, etc.), and one or more containers which contain the
reagents used to reveal the presence of the bound probe or other
SNP detection reagents. The kit can optionally further comprise
compartments and/or reagents for, for example, nucleic acid
amplification or other enzymatic reactions such as primer extension
reactions, hybridization, ligation, electrophoresis (preferably
capillary electrophoresis), mass spectrometry, and/or laser-induced
fluorescent detection. The kit may also include instructions for
using the kit. Exemplary compartmentalized kits include
microfluidic devices known in the art. See, e.g., Weigl et al.,
"Lab-on-a-chip for drug development," Adv Drug Deliv Rev
55(3):349-77 (February 2003). In such microfluidic devices, the
containers may be referred to as, for example, microfluidic
"compartments," "chambers," or "channels."
[0238] Microfluidic devices, which may also be referred to as
"lab-on-a-chip" systems, biomedical micro-electro-mechanical
systems (bioMEMs), or multicomponent integrated systems, are
exemplary kits/systems of the present invention for analyzing SNPs.
Such systems miniaturize and compartmentalize processes such as
probe/target hybridization, nucleic acid amplification, and
capillary electrophoresis reactions in a single functional device.
Such microfluidic devices typically utilize detection reagents in
at least one aspect of the system, and such detection reagents may
be used to detect one or more SNPs of the present invention. One
example of a microfluidic system is disclosed in U.S. Pat. No.
5,589,136, which describes the integration of PCR amplification and
capillary electrophoresis in chips. Exemplary microfluidic systems
comprise a pattern of microchannels designed onto a glass, silicon,
quartz, or plastic wafer included on a microchip. The movements of
the samples may be controlled by electric, electroosmotic or
hydrostatic forces applied across different areas of the microchip
to create functional microscopic valves and pumps with no moving
parts. Varying the voltage can be used as a means to control the
liquid flow at intersections between the micro-machined channels
and to change the liquid flow rate for pumping across different
sections of the microchip. See, for example, U.S. Pat. No.
6,153,073, Dubrow et al., and U.S. Pat. No. 6,156,181, Parce et
al.
[0239] For genotyping SNPs, an exemplary microfluidic system may
integrate, for example, nucleic acid amplification, primer
extension, capillary electrophoresis, and a detection method such
as laser induced fluorescence detection. In a first step of an
exemplary process for using such an exemplary system, nucleic acid
samples are amplified, preferably by PCR. Then, the amplification
products are subjected to automated primer extension reactions
using ddNTPs (specific fluorescence for each ddNTP) and the
appropriate oligonucleotide primers to carry out primer extension
reactions which hybridize just upstream of the targeted SNP. Once
the extension at the 3' end is completed, the primers are separated
from the unincorporated fluorescent ddNTPs by capillary
electrophoresis. The separation medium used in capillary
electrophoresis can be, for example, polyacrylamide,
polyethyleneglycol or dextran. The incorporated ddNTPs in the
single nucleotide primer extension products are identified by
laser-induced fluorescence detection. Such an exemplary microchip
can be used to process, for example, at least 96 to 384 samples, or
more, in parallel.
[0240] Uses of Nucleic Acid Molecules
[0241] The nucleic acid molecules of the present invention have a
variety of uses, especially for the diagnosis, prognosis,
treatment, and prevention of psoriasis, and for predicting drug
response. For example, the nucleic acid molecules of the invention
are useful for predicting an individual's risk for developing
psoriasis, for prognosing the progression of psoriasis (e.g., the
severity or consequences of psoriasis) in an individual, in
evaluating the likelihood of an individual who has psoriasis (or
who is at increased risk for psoriasis) of responding to treatment
(or prevention) of psoriasis with a drug treatment, and/or
predicting the likelihood that the individual will experience
toxicity or other undesirable side effects from the drug treatment,
etc. For example, the nucleic acid molecules are useful as
hybridization probes, such as for genotyping SNPs in messenger RNA,
transcript, cDNA, genomic DNA, amplified DNA or other nucleic acid
molecules, and for isolating full-length cDNA and genomic clones
encoding the variant peptides disclosed in Table 1 as well as their
orthologs.
[0242] A probe can hybridize to any nucleotide sequence along the
entire length of a nucleic acid molecule referred to in Table 1
and/or Table 2. Preferably, a probe of the present invention
hybridizes to a region of a target sequence that encompasses a SNP
position indicated in Table 1 and/or Table 2. More preferably, a
probe hybridizes to a SNP-containing target sequence in a
sequence-specific manner such that it distinguishes the target
sequence from other nucleotide sequences which vary from the target
sequence only by which nucleotide is present at the SNP site. Such
a probe is particularly useful for detecting the presence of a
SNP-containing nucleic acid in a test sample, or for determining
which nucleotide (allele) is present at a particular SNP site
(i.e., genotyping the SNP site).
[0243] A nucleic acid hybridization probe may be used for
determining the presence, level, form, and/or distribution of
nucleic acid expression. The nucleic acid whose level is determined
can be DNA or RNA. Accordingly, probes specific for the SNPs
described herein can be used to assess the presence, expression
and/or gene copy number in a given cell, tissue, or organism. These
uses are relevant for diagnosis of disorders involving an increase
or decrease in gene expression relative to normal levels. In vitro
techniques for detection of mRNA include, for example, Northern
blot hybridizations and in situ hybridizations. In vitro techniques
for detecting DNA include Southern blot hybridizations and in situ
hybridizations. Sambrook and Russell, Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).
[0244] Probes can be used as part of a diagnostic test kit for
identifying cells or tissues in which a variant protein is
expressed, such as by measuring the level of a variant
protein-encoding nucleic acid (e.g., mRNA) in a sample of cells
from a subject or determining if a polynucleotide contains a SNP of
interest.
[0245] Thus, the nucleic acid molecules of the invention can be
used as hybridization probes to detect the SNPs disclosed herein,
thereby determining whether an individual with the polymorphism(s)
is at risk for developing psoriasis (or has already developed early
stage psoriasis), or the likelihood that an individual will respond
positively to a drug treatment (including preventive treatment) of
psoriasis. Detection of a SNP associated with a disease phenotype
provides a diagnostic tool for an active disease and/or genetic
predisposition to the disease.
[0246] Furthermore, the nucleic acid molecules of the invention are
therefore useful for detecting a gene (gene information is
disclosed in Table 2, for example) which contains a SNP disclosed
herein and/or products of such genes, such as expressed mRNA
transcript molecules (transcript information is disclosed in Table
1, for example), and are thus useful for detecting gene expression.
The nucleic acid molecules can optionally be implemented in, for
example, an array or kit format for use in detecting gene
expression.
[0247] The nucleic acid molecules of the invention are also useful
as primers to amplify any given region of a nucleic acid molecule,
particularly a region containing a SNP identified in Table 1 and/or
Table 2.
[0248] The nucleic acid molecules of the invention are also useful
for constructing recombinant vectors (described in greater detail
below). Such vectors include expression vectors that express a
portion of, or all of, any of the variant peptide sequences
referred to in Table 1. Vectors also include insertion vectors,
used to integrate into another nucleic acid molecule sequence, such
as into the cellular genome, to alter in situ expression of a gene
and/or gene product. For example, an endogenous coding sequence can
be replaced via homologous recombination with all or part of the
coding region containing one or more specifically introduced
SNPs.
[0249] The nucleic acid molecules of the invention are also useful
for expressing antigenic portions of the variant proteins,
particularly antigenic portions that contain a variant amino acid
sequence (e.g., an amino acid substitution) caused by a SNP
disclosed in Table 1 and/or Table 2.
[0250] The nucleic acid molecules of the invention are also useful
for constructing vectors containing a gene regulatory region of the
nucleic acid molecules of the present invention.
[0251] The nucleic acid molecules of the invention are also useful
for designing ribozymes corresponding to all, or a part, of an mRNA
molecule expressed from a SNP-containing nucleic acid molecule
described herein.
[0252] The nucleic acid molecules of the invention are also useful
for constructing host cells expressing a part, or all, of the
nucleic acid molecules and variant peptides.
[0253] The nucleic acid molecules of the invention are also useful
for constructing transgenic animals expressing all, or a part, of
the nucleic acid molecules and variant peptides. The production of
recombinant cells and transgenic animals having nucleic acid
molecules which contain the SNPs disclosed in Table 1 and/or Table
2 allows, for example, effective clinical design of treatment
compounds and dosage regimens.
[0254] The nucleic acid molecules of the invention are also useful
in assays for drug screening to identify compounds that, for
example, modulate nucleic acid expression.
[0255] The nucleic acid molecules of the invention are also useful
in gene therapy in patients whose cells have aberrant gene
expression. Thus, recombinant cells, which include a patient's
cells that have been engineered ex vivo and returned to the
patient, can be introduced into an individual where the recombinant
cells produce the desired protein to treat the individual.
[0256] SNP Genotyping Methods
[0257] The process of determining which nucleotide(s) is/are
present at each of one or more SNP positions (such as a SNP
position disclosed in Table 1 and/or Table 2), for either or both
alleles, may be referred to by such phrases as SNP genotyping,
determining the "identity" of a SNP, determining the "content" of a
SNP, or determining which nucleotide(s)/allele(s) is/are present at
a SNP position. Thus, these terms can refer to detecting a single
allele (nucleotide) at a SNP position or can encompass detecting
both alleles (nucleotides) at a SNP position (such as to determine
the homozygous or heterozygous state of a SNP position).
Furthermore, these terms may also refer to detecting an amino acid
residue encoded by a SNP (such as alternative amino acid residues
that are encoded by different codons created by alternative
nucleotides at a SNP position).
[0258] The present invention provides methods of SNP genotyping,
such as for use in evaluating an individual's risk for developing
psoriasis, for evaluating an individual's prognosis for disease
severity and recovery, for predicting the likelihood that an
individual who has previously had psoriasis will have a recurrence
of psoriasis again in the future, for implementing a preventive or
treatment regimen for an individual based on that individual having
an increased susceptibility for developing psoriasis, in evaluating
an individual's likelihood of responding to a drug treatment
(particularly for treating or preventing psoriasis), in selecting a
treatment or preventive regimen (e.g., in deciding whether or not
to administer a drug treatment to an individual having psoriasis,
or who is at increased risk for developing psoriasis in the
future), or in formulating or selecting a particular treatment or
preventive regimen such as dosage and/or frequency of
administration of a treatment or choosing which form/type of a drug
to be administered, such as a particular pharmaceutical composition
or compound, etc.), determining the likelihood of experiencing
toxicity or other undesirable side effects from a drug treatment,
or selecting individuals for a clinical trial of a drug (e.g.,
selecting individuals to participate in the trial who are most
likely to respond positively from the drug treatment and/or
excluding individuals from the trial who are unlikely to respond
positively from the drug treatment based on their SNP genotype(s),
or selecting individuals who are unlikely to respond positively to
a particular drug based on their SNP genotype(s) to participate in
a clinical trial of another type of drug that may benefit them),
etc.
[0259] Nucleic acid samples can be genotyped to determine which
allele(s) is/are present at any given genetic region (e.g., SNP
position) of interest by methods well known in the art. The
neighboring sequence can be used to design SNP detection reagents
such as oligonucleotide probes, which may optionally be implemented
in a kit format. Exemplary SNP genotyping methods are described in
Chen et al., "Single nucleotide polymorphism genotyping:
biochemistry, protocol, cost and throughput," Pharmacogenomics J
3(2):77-96 (2003); Kwok et al., "Detection of single nucleotide
polymorphisms," Curr Issues Mol Biol 5(2):43-60 (April 2003); Shi,
"Technologies for individual genotyping: detection of genetic
polymorphisms in drug targets and disease genes," Am J
Pharmacogenomics 2(3):197-205 (2002); and Kwok, "Methods for
genotyping single nucleotide polymorphisms," Annu Rev Genomics Hum
Genet 2:235-58 (2001). Exemplary techniques for high-throughput SNP
genotyping are described in Marnellos, "High-throughput SNP
analysis for genetic association studies," Curr Opin Drug Discov
Devel 6(3):317-21 (May 2003). Common SNP genotyping methods
include, but are not limited to, TaqMan assays, molecular beacon
assays, nucleic acid arrays, allele-specific primer extension,
allele-specific PCR, arrayed primer extension, homogeneous primer
extension assays, primer extension with detection by mass
spectrometry, pyrosequencing, multiplex primer extension sorted on
genetic arrays, ligation with rolling circle amplification,
homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex
ligation reaction sorted on genetic arrays, restriction-fragment
length polymorphism, single base extension-tag assays, and the
Invader assay. Such methods may be used in combination with
detection mechanisms such as, for example, luminescence or
chemiluminescence detection, fluorescence detection, time-resolved
fluorescence detection, fluorescence resonance energy transfer,
fluorescence polarization, mass spectrometry, and electrical
detection.
[0260] Various methods for detecting polymorphisms include, but are
not limited to, methods in which protection from cleavage agents is
used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes
(Myers et al., Science 230:1242 (1985); Cotton et al., PNAS 85:4397
(1988); and Saleeba et al., Meth. Enzymol 217:286-295 (1992)),
comparison of the electrophoretic mobility of variant and wild type
nucleic acid molecules (Orita et al., PNAS 86:2766 (1989); Cotton
et al., Mutat Res 285:125-144 (1993); and Hayashi et al., Genet
Anal Tech Appl 9:73-79 (1992)), and assaying the movement of
polymorphic or wild-type fragments in polyacrylamide gels
containing a gradient of denaturant using denaturing gradient gel
electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)).
Sequence variations at specific locations can also be assessed by
nuclease protection assays such as RNase and S1 protection or
chemical cleavage methods.
[0261] In a preferred embodiment, SNP genotyping is performed using
the TaqMan assay, which is also known as the 5' nuclease assay
(U.S. Pat. Nos. 5,210,015 and 5,538,848). The TaqMan assay detects
the accumulation of a specific amplified product during PCR. The
TaqMan assay utilizes an oligonucleotide probe labeled with a
fluorescent reporter dye and a quencher dye. The reporter dye is
excited by irradiation at an appropriate wavelength, it transfers
energy to the quencher dye in the same probe via a process called
fluorescence resonance energy transfer (FRET). When attached to the
probe, the excited reporter dye does not emit a signal. The
proximity of the quencher dye to the reporter dye in the intact
probe maintains a reduced fluorescence for the reporter. The
reporter dye and quencher dye may be at the 5' most and the 3' most
ends, respectively, or vice versa. Alternatively, the reporter dye
may be at the 5' or 3' most end while the quencher dye is attached
to an internal nucleotide, or vice versa. In yet another
embodiment, both the reporter and the quencher may be attached to
internal nucleotides at a distance from each other such that
fluorescence of the reporter is reduced.
[0262] During PCR, the 5' nuclease activity of DNA polymerase
cleaves the probe, thereby separating the reporter dye and the
quencher dye and resulting in increased fluorescence of the
reporter. Accumulation of PCR product is detected directly by
monitoring the increase in fluorescence of the reporter dye. The
DNA polymerase cleaves the probe between the reporter dye and the
quencher dye only if the probe hybridizes to the target
SNP-containing template which is amplified during PCR, and the
probe is designed to hybridize to the target SNP site only if a
particular SNP allele is present.
[0263] Preferred TaqMan primer and probe sequences can readily be
determined using the SNP and associated nucleic acid sequence
information provided herein. A number of computer programs, such as
Primer Express (Applied Biosystems, Foster City, Calif.), can be
used to rapidly obtain optimal primer/probe sets. It will be
apparent to one of skill in the art that such primers and probes
for detecting the SNPs of the present invention are useful in, for
example, screening for individuals who are susceptible to
developing psoriasis and related pathologies, or in screening
individuals who have psoriasis (or who are susceptible to
psoriasis) for their likelihood of responding to a drug treatment.
These probes and primers can be readily incorporated into a kit
format. The present invention also includes modifications of the
Taqman assay well known in the art such as the use of Molecular
Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other
variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).
[0264] Another preferred method for genotyping the SNPs of the
present invention is the use of two oligonucleotide probes in an
OLA (see, e.g., U.S. Pat. No. 4,988,617). In this method, one probe
hybridizes to a segment of a target nucleic acid with its 3' most
end aligned with the SNP site. A second probe hybridizes to an
adjacent segment of the target nucleic acid molecule directly 3' to
the first probe. The two juxtaposed probes hybridize to the target
nucleic acid molecule, and are ligated in the presence of a linking
agent such as a ligase if there is perfect complementarity between
the 3' most nucleotide of the first probe with the SNP site. If
there is a mismatch, ligation would not occur. After the reaction,
the ligated probes are separated from the target nucleic acid
molecule, and detected as indicators of the presence of a SNP.
[0265] The following patents, patent applications, and published
international patent applications, which are all hereby
incorporated by reference, provide additional information
pertaining to techniques for carrying out various types of OLA. The
following U.S. patents describe OLA strategies for performing SNP
detection: U.S. Pat. Nos. 6,027,889; 6,268,148; 5,494,810;
5,830,711 and 6,054,564. WO 97/31256 and WO 00/56927 describe OLA
strategies for performing SNP detection using universal arrays,
wherein a zipcode sequence can be introduced into one of the
hybridization probes, and the resulting product, or amplified
product, hybridized to a universal zip code array. U.S. application
US01/17329 (and Ser. No. 09/584,905) describes OLA (or LDR)
followed by PCR, wherein zipcodes are incorporated into OLA probes,
and amplified PCR products are determined by electrophoretic or
universal zipcode array readout. U.S. applications 60/427,818,
60/445,636, and 60/445,494 describe SNPlex methods and software for
multiplexed SNP detection using OLA followed by PCR, wherein
zipcodes are incorporated into OLA probes, and amplified PCR
products are hybridized with a zipchute reagent, and the identity
of the SNP determined from electrophoretic readout of the zipchute.
In some embodiments, OLA is carried out prior to PCR (or another
method of nucleic acid amplification). In other embodiments, PCR
(or another method of nucleic acid amplification) is carried out
prior to OLA.
[0266] Another method for SNP genotyping is based on mass
spectrometry. Mass spectrometry takes advantage of the unique mass
of each of the four nucleotides of DNA. SNPs can be unambiguously
genotyped by mass spectrometry by measuring the differences in the
mass of nucleic acids having alternative SNP alleles. MALDI-TOF
(Matrix Assisted Laser Desorption Ionization-Time of Flight) mass
spectrometry technology is preferred for extremely precise
determinations of molecular mass, such as SNPs. Numerous approaches
to SNP analysis have been developed based on mass spectrometry.
Preferred mass spectrometry-based methods of SNP genotyping include
primer extension assays, which can also be utilized in combination
with other approaches, such as traditional gel-based formats and
microarrays.
[0267] Typically, the primer extension assay involves designing and
annealing a primer to a template PCR amplicon upstream (5') from a
target SNP position. A mix of dideoxynucleotide triphosphates
(ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to
a reaction mixture containing template (e.g., a SNP-containing
nucleic acid molecule which has typically been amplified, such as
by PCR), primer, and DNA polymerase. Extension of the primer
terminates at the first position in the template where a nucleotide
complementary to one of the ddNTPs in the mix occurs. The primer
can be either immediately adjacent (i.e., the nucleotide at the 3'
end of the primer hybridizes to the nucleotide next to the target
SNP site) or two or more nucleotides removed from the SNP position.
If the primer is several nucleotides removed from the target SNP
position, the only limitation is that the template sequence between
the 3' end of the primer and the SNP position cannot contain a
nucleotide of the same type as the one to be detected, or this will
cause premature termination of the extension primer. Alternatively,
if all four ddNTPs alone, with no dNTPs, are added to the reaction
mixture, the primer will always be extended by only one nucleotide,
corresponding to the target SNP position. In this instance, primers
are designed to bind one nucleotide upstream from the SNP position
(i.e., the nucleotide at the 3' end of the primer hybridizes to the
nucleotide that is immediately adjacent to the target SNP site on
the 5' side of the target SNP site). Extension by only one
nucleotide is preferable, as it minimizes the overall mass of the
extended primer, thereby increasing the resolution of mass
differences between alternative SNP nucleotides. Furthermore,
mass-tagged ddNTPs can be employed in the primer extension
reactions in place of unmodified ddNTPs. This increases the mass
difference between primers extended with these ddNTPs, thereby
providing increased sensitivity and accuracy, and is particularly
useful for typing heterozygous base positions. Mass-tagging also
alleviates the need for intensive sample-preparation procedures and
decreases the necessary resolving power of the mass
spectrometer.
[0268] The extended primers can then be purified and analyzed by
MALDI-TOF mass spectrometry to determine the identity of the
nucleotide present at the target SNP position. In one method of
analysis, the products from the primer extension reaction are
combined with light absorbing crystals that form a matrix. The
matrix is then hit with an energy source such as a laser to ionize
and desorb the nucleic acid molecules into the gas-phase. The
ionized molecules are then ejected into a flight tube and
accelerated down the tube towards a detector. The time between the
ionization event, such as a laser pulse, and collision of the
molecule with the detector is the time of flight of that molecule.
The time of flight is precisely correlated with the mass-to-charge
ratio (m/z) of the ionized molecule. Ions with smaller m/z travel
down the tube faster than ions with larger m/z and therefore the
lighter ions reach the detector before the heavier ions. The
time-of-flight is then converted into a corresponding, and highly
precise, m/z. In this manner, SNPs can be identified based on the
slight differences in mass, and the corresponding time of flight
differences, inherent in nucleic acid molecules having different
nucleotides at a single base position. For further information
regarding the use of primer extension assays in conjunction with
MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise et
al., "A standard protocol for single nucleotide primer extension in
the human genome using matrix-assisted laser desorption/ionization
time-of-flight mass spectrometry," Rapid Commun Mass Spectrom
17(11):1195-202 (2003).
[0269] The following references provide further information
describing mass spectrometry-based methods for SNP genotyping:
Bocker, "SNP and mutation discovery using base-specific cleavage
and MALDI-TOF mass spectrometry," Bioinformatics 19 Suppl 1:144-153
(July 2003); Storm et al., "MALDI-TOF mass spectrometry-based SNP
genotyping," Methods Mol Biol 212:241-62 (2003); Jurinke et al.,
"The use of Mass ARRAY technology for high throughput genotyping,"
Adv Biochem Eng Biotechnol 77:57-74 (2002); and Jurinke et al.,
"Automated genotyping using the DNA MassArray technology," Methods
Mol Biol 187:179-92 (2002).
[0270] SNPs can also be scored by direct DNA sequencing. A variety
of automated sequencing procedures can be utilized (e.g.
Biotechniques 19:448 (1995)), including sequencing by mass
spectrometry. See, e.g., PCT International Publication No. WO
94/16101; Cohen et al., Adv Chromatogr 36:127-162 (1996); and
Griffin et al., Appl Biochem Biotechnol 38:147-159 (1993). The
nucleic acid sequences of the present invention enable one of
ordinary skill in the art to readily design sequencing primers for
such automated sequencing procedures. Commercial instrumentation,
such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1
DNA Analyzers (Foster City, Calif.), is commonly used in the art
for automated sequencing.
[0271] Other methods that can be used to genotype the SNPs of the
present invention include single-strand conformational polymorphism
(SSCP), and denaturing gradient gel electrophoresis (DGGE). Myers
et al., Nature 313:495 (1985). SSCP identifies base differences by
alteration in electrophoretic migration of single stranded PCR
products, as described in Orita et al., Proc. Nat. Acad.
Single-stranded PCR products can be generated by heating or
otherwise denaturing double stranded PCR products. Single-stranded
nucleic acids may refold or form secondary structures that are
partially dependent on the base sequence. The different
electrophoretic mobilities of single-stranded amplification
products are related to base-sequence differences at SNP positions.
DGGE differentiates SNP alleles based on the different
sequence-dependent stabilities and melting properties inherent in
polymorphic DNA and the corresponding differences in
electrophoretic migration patterns in a denaturing gradient gel.
PCR Technology: Principles and Applications for DNA Amplification
Chapter 7, Erlich, ed., W.H. Freeman and Co, N.Y. (1992).
[0272] Sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can
also be used to score SNPs based on the development or loss of a
ribozyme cleavage site. Perfectly matched sequences can be
distinguished from mismatched sequences by nuclease cleavage
digestion assays or by differences in melting temperature. If the
SNP affects a restriction enzyme cleavage site, the SNP can be
identified by alterations in restriction enzyme digestion patterns,
and the corresponding changes in nucleic acid fragment lengths
determined by gel electrophoresis.
[0273] SNP genotyping can include the steps of, for example,
collecting a biological sample from a human subject (e.g., sample
of tissues, cells, fluids, secretions, etc.), isolating nucleic
acids (e.g., genomic DNA, mRNA or both) from the cells of the
sample, contacting the nucleic acids with one or more primers which
specifically hybridize to a region of the isolated nucleic acid
containing a target SNP under conditions such that hybridization
and amplification of the target nucleic acid region occurs, and
determining the nucleotide present at the SNP position of interest,
or, in some assays, detecting the presence or absence of an
amplification product (assays can be designed so that hybridization
and/or amplification will only occur if a particular SNP allele is
present or absent). In some assays, the size of the amplification
product is detected and compared to the length of a control sample;
for example, deletions and insertions can be detected by a change
in size of the amplified product compared to a normal genotype.
[0274] SNP genotyping is useful for numerous practical
applications, as described below. Examples of such applications
include, but are not limited to, SNP-disease association analysis,
disease predisposition screening, disease diagnosis, disease
prognosis, disease progression monitoring, determining therapeutic
strategies based on an individual's genotype ("pharmacogenomics"),
developing therapeutic agents based on SNP genotypes associated
with a disease or likelihood of responding to a drug, stratifying
patient populations for clinical trials of a therapeutic,
preventive, or diagnostic agent, predicting the likelihood that an
individual will experience toxic side effects from a therapeutic
agent, and human identification applications such as forensics.
[0275] Analysis of Genetic Associations between SNPs and Phenotypic
Traits
[0276] SNP genotyping for disease diagnosis, disease predisposition
screening, disease prognosis, determining drug responsiveness
(pharmacogenomics), drug toxicity screening, and other uses
described herein, typically relies on initially establishing a
genetic association between one or more specific SNPs and the
particular phenotypic traits of interest.
[0277] Different study designs may be used for genetic association
studies. Modern Epidemiology 609-622, Lippincott, Williams &
Wilkins (1998). Observational studies are most frequently carried
out in which the response of the patients is not interfered with.
The first type of observational study identifies a sample of
persons in whom the suspected cause of the disease is present and
another sample of persons in whom the suspected cause is absent,
and then the frequency of development of disease in the two samples
is compared. These sampled populations are called cohorts, and the
study is a prospective study. The other type of observational study
is case-control or a retrospective study. In typical case-control
studies, samples are collected from individuals with the phenotype
of interest (cases) such as certain manifestations of a disease,
and from individuals without the phenotype (controls) in a
population (target population) that conclusions are to be drawn
from. Then the possible causes of the disease are investigated
retrospectively. As the time and costs of collecting samples in
case-control studies are considerably less than those for
prospective studies, case-control studies are the more commonly
used study design in genetic association studies, at least during
the exploration and discovery stage.
[0278] In both types of observational studies, there may be
potential confounding factors that should be taken into
consideration. Confounding factors are those that are associated
with both the real cause(s) of the disease and the disease itself,
and they include demographic information such as age, gender,
ethnicity as well as environmental factors. When confounding
factors are not matched in cases and controls in a study, and are
not controlled properly, spurious association results can arise. If
potential confounding factors are identified, they should be
controlled for by analysis methods explained below.
[0279] In a genetic association study, the cause of interest to be
tested is a certain allele or a SNP or a combination of alleles or
a haplotype from several SNPs. Thus, tissue specimens (e.g., whole
blood) from the sampled individuals may be collected and genomic
DNA genotyped for the SNP(s) of interest. In addition to the
phenotypic trait of interest, other information such as demographic
(e.g., age, gender, ethnicity, etc.), clinical, and environmental
information that may influence the outcome of the trait can be
collected to further characterize and define the sample set. In
many cases, these factors are known to be associated with diseases
and/or SNP allele frequencies. There are likely gene-environment
and/or gene-gene interactions as well. Analysis methods to address
gene-environment and gene-gene interactions (for example, the
effects of the presence of both susceptibility alleles at two
different genes can be greater than the effects of the individual
alleles at two genes combined) are discussed below.
[0280] After all the relevant phenotypic and genotypic information
has been obtained, statistical analyses are carried out to
determine if there is any significant correlation between the
presence of an allele or a genotype with the phenotypic
characteristics of an individual. Preferably, data inspection and
cleaning are first performed before carrying out statistical tests
for genetic association. Epidemiological and clinical data of the
samples can be summarized by descriptive statistics with tables and
graphs. Data validation is preferably performed to check for data
completion, inconsistent entries, and outliers. Chi-squared tests
and t-tests (Wilcoxon rank-sum tests if distributions are not
normal) may then be used to check for significant differences
between cases and controls for discrete and continuous variables,
respectively. To ensure genotyping quality, Hardy-Weinberg
disequilibrium tests can be performed on cases and controls
separately. Significant deviation from Hardy-Weinberg equilibrium
(HWE) in both cases and controls for individual markers can be
indicative of genotyping errors. If HWE is violated in a majority
of markers, it is indicative of population substructure that should
be further investigated. Moreover, Hardy-Weinberg disequilibrium in
cases only can indicate genetic association of the markers with the
disease. B. Weir, Genetic Data Analysis, Sinauer (1990).
[0281] To test whether an allele of a single SNP is associated with
the case or control status of a phenotypic trait, one skilled in
the art can compare allele frequencies in cases and controls.
Standard chi-squared tests and Fisher exact tests can be carried
out on a 2.times.2 table (2 SNP alleles.times.2 outcomes in the
categorical trait of interest). To test whether genotypes of a SNP
are associated, chi-squared tests can be carried out on a 3.times.2
table (3 genotypes.times.2 outcomes). Score tests are also carried
out for genotypic association to contrast the three genotypic
frequencies (major homozygotes, heterozygotes and minor
homozygotes) in cases and controls, and to look for trends using 3
different modes of inheritance, namely dominant (with contrast
coefficients 2, -1, -1), additive or allelic (with contrast
coefficients 1, 0, -1) and recessive (with contrast coefficients 1,
1, -2). Odds ratios for minor versus major alleles, and odds ratios
for heterozygote and homozygote variants versus the wild type
genotypes are calculated with the desired confidence limits,
usually 95%.
[0282] In order to control for confounders and to test for
interaction and effect modifiers, stratified analyses may be
performed using stratified factors that are likely to be
confounding, including demographic information such as age,
ethnicity, and gender, or an interacting element or effect
modifier, such as a known major gene (e.g., APOE for Alzheimer's
disease or HLA genes for autoimmune diseases), or environmental
factors such as smoking in lung cancer. Stratified association
tests may be carried out using Cochran-Mantel-Haenszel tests that
take into account the ordinal nature of genotypes with 0, 1, and 2
variant alleles. Exact tests by StatXact may also be performed when
computationally possible. Another way to adjust for confounding
effects and test for interactions is to perform stepwise multiple
logistic regression analysis using statistical packages such as SAS
or R. Logistic regression is a model-building technique in which
the best fitting and most parsimonious model is built to describe
the relation between the dichotomous outcome (for instance, getting
a certain disease or not) and a set of independent variables (for
instance, genotypes of different associated genes, and the
associated demographic and environmental factors). The most common
model is one in which the logit transformation of the odds ratios
is expressed as a linear combination of the variables (main
effects) and their cross-product terms (interactions). Hosmer and
Lemeshow, Applied Logistic Regression, Wiley (2000). To test
whether a certain variable or interaction is significantly
associated with the outcome, coefficients in the model are first
estimated and then tested for statistical significance of their
departure from zero.
[0283] In addition to performing association tests one marker at a
time, haplotype association analysis may also be performed to study
a number of markers that are closely linked together. Haplotype
association tests can have better power than genotypic or allelic
association tests when the tested markers are not the
disease-causing mutations themselves but are in linkage
disequilibrium with such mutations. The test will even be more
powerful if the disease is indeed caused by a combination of
alleles on a haplotype (e.g., APOE is a haplotype formed by 2 SNPs
that are very close to each other). In order to perform haplotype
association effectively, marker-marker linkage disequilibrium
measures, both D' and r.sup.2, are typically calculated for the
markers within a gene to elucidate the haplotype structure. Recent
studies in linkage disequilibrium indicate that SNPs within a gene
are organized in block pattern, and a high degree of linkage
disequilibrium exists within blocks and very little linkage
disequilibrium exists between blocks. Daly et al, Nature Genetics
29:232-235 (2001). Haplotype association with the disease status
can be performed using such blocks once they have been
elucidated.
[0284] Haplotype association tests can be carried out in a similar
fashion as the allelic and genotypic association tests. Each
haplotype in a gene is analogous to an allele in a multi-allelic
marker. One skilled in the art can either compare the haplotype
frequencies in cases and controls or test genetic association with
different pairs of haplotypes. It has been proposed that score
tests can be done on haplotypes using the program "haplo.score."
Schaid et al, Am J Hum Genet 70:425-434 (2002). In that method,
haplotypes are first inferred by EM algorithm and score tests are
carried out with a generalized linear model (GLM) framework that
allows the adjustment of other factors.
[0285] An important decision in the performance of genetic
association tests is the determination of the significance level at
which significant association can be declared when the P value of
the tests reaches that level. In an exploratory analysis where
positive hits will be followed up in subsequent confirmatory
testing, an unadjusted P value<0.2 (a significance level on the
lenient side), for example, may be used for generating hypotheses
for significant association of a SNP with certain phenotypic
characteristics of a disease. It is preferred that a
p-value<0.05 (a significance level traditionally used in the
art) is achieved in order for a SNP to be considered to have an
association with a disease. It is more preferred that a
p-value<0.01 (a significance level on the stringent side) is
achieved for an association to be declared. When hits are followed
up in confirmatory analyses in more samples of the same source or
in different samples from different sources, adjustment for
multiple testing will be performed as to avoid excess number of
hits while maintaining the experiment-wide error rates at 0.05.
While there are different methods to adjust for multiple testing to
control for different kinds of error rates, a commonly used but
rather conservative method is Bonferroni correction to control the
experiment-wise or family-wise error rate. Westfall et al.,
Multiple comparisons and multiple tests, SAS Institute (1999).
Permutation tests to control for the false discovery rates, FDR,
can be more powerful. Benjamini and Hochberg, Journal of the Royal
Statistical Society, Series B 57:1289-1300 (1995); Westfall and
Young, Resampling-based Multiple Testing, Wiley (1993). Such
methods to control for multiplicity would be preferred when the
tests are dependent and controlling for false discovery rates is
sufficient as opposed to controlling for the experiment-wise error
rates.
[0286] In replication studies using samples from different
populations after statistically significant markers have been
identified in the exploratory stage, meta-analyses can then be
performed by combining evidence of different studies. Modern
Epidemiology 643-673, Lippincott, Williams & Wilkins (1998). If
available, association results known in the art for the same SNPs
can be included in the meta-analyses.
[0287] Since both genotyping and disease status classification can
involve errors, sensitivity analyses may be performed to see how
odds ratios and p-values would change upon various estimates on
genotyping and disease classification error rates.
[0288] It has been well known that subpopulation-based sampling
bias between cases and controls can lead to spurious results in
case-control association studies when prevalence of the disease is
associated with different subpopulation groups. Ewens and Spielman,
Am J Hum Genet 62:450-458 (1995). Such bias can also lead to a loss
of statistical power in genetic association studies. To detect
population stratification, Pritchard and Rosenberg suggested typing
markers that are unlinked to the disease and using results of
association tests on those markers to determine whether there is
any population stratification. Pritchard et al., Am J Hum Gen
65:220-228 (1999). When stratification is detected, the genomic
control (GC) method as proposed by Devlin and Roeder can be used to
adjust for the inflation of test statistics due to population
stratification. Devlin et al., Biometrics 55:997-1004 (1999). The
GC method is robust to changes in population structure levels as
well as being applicable to DNA pooling designs. Devlin et al.,
Genet Epidem 21:273-284 (2001).
[0289] While Pritchard's method recommended using 15-20 unlinked
microsatellite markers, it suggested using more than 30 biallelic
markers to get enough power to detect population stratification.
For the GC method, it has been shown that about 60-70 biallelic
markers are sufficient to estimate the inflation factor for the
test statistics due to population stratification. Bacanu et al., Am
J Hum Genet 66:1933-1944 (2000). Hence, 70 intergenic SNPs can be
chosen in unlinked regions as indicated in a genome scan. Kehoe et
al., Hum Mol Genet 8:237-245 (1999).
[0290] Once individual risk factors, genetic or non-genetic, have
been found for the predisposition to disease, the next step is to
set up a classification/prediction scheme to predict the category
(for instance, disease or no-disease) that an individual will be in
depending on his genotypes of associated SNPs and other non-genetic
risk factors. Logistic regression for discrete trait and linear
regression for continuous trait are standard techniques for such
tasks. Draper and Smith, Applied Regression Analysis, Wiley (1998).
Moreover, other techniques can also be used for setting up
classification. Such techniques include, but are not limited to,
MART, CART, neural network, and discriminant analyses that are
suitable for use in comparing the performance of different methods.
The Elements of Statistical Learning, Hastie, Tibshirani &
Friedman, Springer (2002).
[0291] Disease Diagnosis and Predisposition Screening
[0292] Information on association/correlation between genotypes and
disease-related phenotypes can be exploited in several ways. For
example, in the case of a highly statistically significant
association between one or more SNPs with predisposition to a
disease for which treatment is available, detection of such a
genotype pattern in an individual may justify immediate
administration of treatment, or at least the institution of regular
monitoring of the individual. Detection of the susceptibility
alleles associated with serious disease in a couple contemplating
having children may also be valuable to the couple in their
reproductive decisions. In the case of a weaker but still
statistically significant association between a SNP and a human
disease, immediate therapeutic intervention or monitoring may not
be justified after detecting the susceptibility allele or SNP.
Nevertheless, the subject can be motivated to begin simple
life-style changes (e.g., diet, exercise) that can be accomplished
at little or no cost to the individual but would confer potential
benefits in reducing the risk of developing conditions for which
that individual may have an increased risk by virtue of having the
risk allele(s).
[0293] The SNPs of the invention may contribute to the development
of psoriasis, or to responsiveness of an individual to a drug
treatment, in different ways. Some polymorphisms occur within a
protein coding sequence and contribute to disease phenotype by
affecting protein structure. Other polymorphisms occur in noncoding
regions but may exert phenotypic effects indirectly via influence
on, for example, replication, transcription, and/or translation. A
single SNP may affect more than one phenotypic trait. Likewise, a
single phenotypic trait may be affected by multiple SNPs in
different genes.
[0294] As used herein, the terms "diagnose," "diagnosis," and
"diagnostics" include, but are not limited to, any of the
following: detection of psoriasis that an individual may presently
have, predisposition/susceptibility/predictive screening (i.e.,
determining whether an individual has an increased or decreased
risk of developing psoriasis in the future), prognosing the future
course of psoriasis or recurrence of psoriasis in an individual,
determining a particular type or subclass of psoriasis in an
individual who currently or previously had psoriasis, confirming or
reinforcing a previously made diagnosis of psoriasis, evaluating an
individual's likelihood of responding positively to a particular
treatment or therapeutic agent (particularly treatment or
prevention of psoriasis), determining or selecting a therapeutic or
preventive strategy that an individual is most likely to positively
respond to (e.g., selecting a particular therapeutic agent, or
combination of therapeutic agents, or determining a dosing regimen,
etc.), classifying (or confirming/reinforcing) an individual as a
responder/non-responder (or determining a particular subtype of
responder/non-responder) with respect to the individual's response
to a drug treatment, and predicting whether a patient is likely to
experience toxic effects from a particular treatment or therapeutic
compound. Such diagnostic uses can be based on the SNPs
individually or in a unique combination or SNP haplotypes of the
present invention.
[0295] Haplotypes are particularly useful in that, for example,
fewer SNPs can be genotyped to determine if a particular genomic
region harbors a locus that influences a particular phenotype, such
as in linkage disequilibrium-based SNP association analysis.
[0296] Linkage disequilibrium (LD) refers to the co-inheritance of
alleles (e.g., alternative nucleotides) at two or more different
SNP sites at frequencies greater than would be expected from the
separate frequencies of occurrence of each allele in a given
population. The expected frequency of co-occurrence of two alleles
that are inherited independently is the frequency of the first
allele multiplied by the frequency of the second allele. Alleles
that co-occur at expected frequencies are said to be in "linkage
equilibrium." In contrast, LD refers to any non-random genetic
association between allele(s) at two or more different SNP sites,
which is generally due to the physical proximity of the two loci
along a chromosome. LD can occur when two or more SNPs sites are in
close physical proximity to each other on a given chromosome and
therefore alleles at these SNP sites will tend to remain
unseparated for multiple generations with the consequence that a
particular nucleotide (allele) at one SNP site will show a
non-random association with a particular nucleotide (allele) at a
different SNP site located nearby. Hence, genotyping one of the SNP
sites will give almost the same information as genotyping the other
SNP site that is in LD.
[0297] Various degrees of LD can be encountered between two or more
SNPs with the result being that some SNPs are more closely
associated (i.e., in stronger LD) than others. Furthermore, the
physical distance over which LD extends along a chromosome differs
between different regions of the genome, and therefore the degree
of physical separation between two or more SNP sites necessary for
LD to occur can differ between different regions of the genome.
[0298] For diagnostic purposes and similar uses, if a particular
SNP site is found to be useful for, for example, predicting an
individual's susceptibility to psoriasis or an individual's
response to a drug treatment, then the skilled artisan would
recognize that other SNP sites which are in LD with this SNP site
would also be useful for the same purposes. Thus, polymorphisms
(e.g., SNPs and/or haplotypes) that are not the actual
disease-causing (causative) polymorphisms, but are in LD with such
causative polymorphisms, are also useful. In such instances, the
genotype of the polymorphism(s) that is/are in LD with the
causative polymorphism is predictive of the genotype of the
causative polymorphism and, consequently, predictive of the
phenotype (e.g., psoriasis, or responder/non-responder to a drug
treatment) that is influenced by the causative SNP(s). Therefore,
polymorphic markers that are in LD with causative polymorphisms are
useful as diagnostic markers, and are particularly useful when the
actual causative polymorphism(s) is/are unknown.
[0299] Examples of polymorphisms that can be in LD with one or more
causative polymorphisms (and/or in LD with one or more
polymorphisms that have a significant statistical association with
a condition) and therefore useful for diagnosing the same condition
that the causative/associated SNP(s) is used to diagnose, include
other SNPs in the same gene, protein-coding, or mRNA
transcript-coding region as the causative/associated SNP, other
SNPs in the same exon or same intron as the causative/associated
SNP, other SNPs in the same haplotype block as the
causative/associated SNP, other SNPs in the same intergenic region
as the causative/associated SNP, SNPs that are outside but near a
gene (e.g., within 6 kb on either side, 5' or 3', of a gene
boundary) that harbors a causative/associated SNP, etc. Such useful
LD SNPs can be selected from among the SNPs disclosed in Tables 1
and 2, for example.
[0300] Linkage disequilibrium in the human genome is reviewed in
Wall et al., "Haplotype blocks and linkage disequilibrium in the
human genome," Nat Rev Genet 4(8):587-97 (August 2003); Garner et
al., "On selecting markers for association studies: patterns of
linkage disequilibrium between two and three diallelic loci," Genet
Epidemiol 24(1):57-67 (January 2003); Ardlie et al., "Patterns of
linkage disequilibrium in the human genome," Nat Rev Genet
3(4):299-309 (April 2002); erratum in Nat Rev Genet 3(7):566 (July
2002); and Remm et al., "High-density genotyping and linkage
disequilibrium in the human genome using chromosome 22 as a model,"
Curr Opin Chem Biol 6(1):24-30 (February 2002); J. B. S. Haldane,
"The combination of linkage values, and the calculation of
distances between the loci of linked factors," J Genet 8:299-309
(1919); G. Mendel, Versuche uber Pflanzen-Hybriden. Verhandlungen
des naturforschenden Vereines in Brunn (Proceedings of the Natural
History Society of Brunn) (1866); Genes IV, B. Lewin, ed., Oxford
University Press, N.Y. (1990); D. L. Hartl and A. G. Clark
Principles of Population Genetics 2.sup.nd ed., Sinauer Associates,
Inc., Mass. (1989); J. H. Gillespie Population Genetics: A Concise
Guide. 2.sup.nd ed., Johns Hopkins University Press (2004); R. C.
Lewontin, "The interaction of selection and linkage. I. General
considerations; heterotic models," Genetics 49:49-67 (1964); P. G.
Hoel, Introduction to Mathematical Statistics 2.sup.nd ed., John
Wiley & Sons, Inc., N.Y. (1954); R. R. Hudson, "Two-locus
sampling distributions and their application," Genetics
159:1805-1817 (2001); A. P. Dempster, N. M. Laird, D. B. Rubin,
"Maximum likelihood from incomplete data via the EM algorithm," J R
Stat Soc 39:1-38 (1977); L. Excoffier, M. Slatkin,
"Maximum-likelihood estimation of molecular haplotype frequencies
in a diploid population," Mol Biol Evol 12(5):921-927 (1995); D. A.
Tregouet, S. Escolano, L. Tiret, A. Mallet, J. L. Golmard, "A new
algorithm for haplotype-based association analysis: the
Stochastic-EM algorithm," Ann Hum Genet 68(Pt 2):165-177 (2004); A.
D. Long and C. H. Langley C H, "The power of association studies to
detect the contribution of candidate genetic loci to variation in
complex traits," Genome Research 9:720-731 (1999); A. Agresti,
Categorical Data Analysis, John Wiley & Sons, Inc., N.Y.
(1990); K. Lange, Mathematical and Statistical Methods for Genetic
Analysis, Springer-Verlag New York, Inc., N.Y. (1997); The
International HapMap Consortium, "The International HapMap
Project," Nature 426:789-796 (2003); The International HapMap
Consortium, "A haplotype map of the human genome," Nature
437:1299-1320 (2005); G. A. Thorisson, A. V. Smith, L. Krishnan, L.
D. Stein, "The International HapMap Project Web Site," Genome
Research 15:1591-1593 (2005); G. McVean, C. C. A. Spencer, R.
Chaix, "Perspectives on human genetic variation from the HapMap
project," PLoS Genetics 1(4):413-418 (2005); J. N. Hirschhorn, M.
J. Daly, "Genome-wide association studies for common diseases and
complex traits," Nat Genet 6:95-108 (2005); S. J. Schrodi, "A
probabilistic approach to large-scale association scans: a
semi-Bayesian method to detect disease-predisposing alleles," SAGMB
4(1):31 (2005); W. Y. S. Wang, B. J. Barratt, D. G. Clayton, J. A.
Todd, "Genome-wide association studies: theoretical and practical
concerns," Nat Rev Genet 6:109-118 (2005); J. K. Pritchard, M.
Przeworski, "Linkage disequilibrium in humans: models and data," Am
J Hum Genet 69:1-14 (2001).
[0301] As discussed above, one aspect of the present invention is
the discovery that SNPs that are in certain LD distance with an
interrogated SNP can also be used as valid markers for determining
whether an individual has an increased or decreased risk of having
or developing psoriasis. As used herein, the term "interrogated
SNP" refers to SNPs that have been found to be associated with an
increased or decreased risk of disease using genotyping results and
analysis, or other appropriate experimental method as exemplified
in the working examples described in this application. As used
herein, the term "LD SNP" refers to a SNP that has been
characterized as a SNP associating with an increased or decreased
risk of diseases due to their being in LD with the "interrogated
SNP" under the methods of calculation described in the application.
Below, applicants describe the methods of calculation with which
one of ordinary skilled in the art may determine if a particular
SNP is in LD with an interrogated SNP. The parameter r.sup.2 is
commonly used in the genetics art to characterize the extent of
linkage disequilibrium between markers (Hudson, 2001). As used
herein, the term "in LD with" refers to a particular SNP that is
measured at above the threshold of a parameter such as r.sup.2 with
an interrogated SNP.
[0302] It is now common place to directly observe genetic variants
in a sample of chromosomes obtained from a population. Suppose one
has genotype data at two genetic markers located on the same
chromosome, for the markers A and B. Further suppose that two
alleles segregate at each of these two markers such that alleles
A.sub.1 and A.sub.2 can be found at marker A and alleles B.sub.1
and B.sub.2 at marker B. Also assume that these two markers are on
a human autosome. If one is to examine a specific individual and
find that they are heterozygous at both markers, such that their
two-marker genotype is A.sub.1A.sub.2B.sub.1B.sub.2, then there are
two possible configurations: the individual in question could have
the alleles A.sub.1B.sub.1 on one chromosome and A.sub.2B.sub.2 on
the remaining chromosome; alternatively, the individual could have
alleles A.sub.1B.sub.2 on one chromosome and A.sub.2B.sub.1 on the
other. The arrangement of alleles on a chromosome is called a
haplotype. In this illustration, the individual could have
haplotypes A.sub.1B.sub.1/A.sub.2B.sub.2 or
A.sub.1B.sub.2/A.sub.2B.sub.1 (see Hartl and Clark (1989) for a
more complete description). The concept of linkage equilibrium
relates the frequency of haplotypes to the allele frequencies.
[0303] Assume that a sample of individuals is selected from a
larger population. Considering the two markers described above,
each having two alleles, there are four possible haplotypes:
A.sub.1B.sub.1, A.sub.1B.sub.2, A.sub.2B.sub.1 and A.sub.2B.sub.2.
Denote the frequencies of these four haplotypes with the following
notation.
P.sub.11=freq(A.sub.1B.sub.1) (1)
P.sub.12=freq(A.sub.1B.sub.2) (2)
P.sub.21=freq(A.sub.2B.sub.1) (3)
P.sub.22=freq(A.sub.2B.sub.2) (4)
The allele frequencies at the two markers are then the sum of
different haplotype frequencies, it is straightforward to write
down a similar set of equations relating single-marker allele
frequencies to two-marker haplotype frequencies:
p.sub.1=freq(A.sub.1)=P.sub.11+P.sub.12 (5)
p.sub.2=freq(A.sub.2)=P.sub.21+P.sub.22 (6)
q.sub.1=freq(B.sub.1)=P.sub.11+P.sub.21 (7)
q.sub.2=freq(B.sub.2)=P.sub.12+P.sub.22 (8)
Note that the four haplotype frequencies and the allele frequencies
at each marker must sum to a frequency of 1.
P.sub.11+P.sub.12+P.sub.21+P.sub.22=1 (9)
p.sub.1+p.sub.2=1 (10)
q.sub.1+q.sub.2=1 (11)
If there is no correlation between the alleles at the two markers,
one would expect that the frequency of the haplotypes would be
approximately the product of the composite alleles. Therefore,
P.sub.11.apprxeq.p.sub.1q.sub.1 (12)
P.sub.12.apprxeq.p.sub.1q.sub.2 (13)
P.sub.21.apprxeq.p.sub.2q.sub.1 (14)
P.sub.22.apprxeq.p.sub.2q.sub.2 (15)
These approximating equations (12)-(15) represent the concept of
linkage equilibrium where there is independent assortment between
the two markers--the alleles at the two markers occur together at
random. These are represented as approximations because linkage
equilibrium and linkage disequilibrium are concepts typically
thought of as properties of a sample of chromosomes; and as such
they are susceptible to stochastic fluctuations due to the sampling
process. Empirically, many pairs of genetic markers will be in
linkage equilibrium, but certainly not all pairs.
[0304] Having established the concept of linkage equilibrium above,
applicants can now describe the concept of linkage disequilibrium
(LD), which is the deviation from linkage equilibrium. Since the
frequency of the A.sub.1B.sub.1 haplotype is approximately the
product of the allele frequencies for A.sub.1 and B.sub.1 under the
assumption of linkage equilibrium as stated mathematically in (12),
a simple measure for the amount of departure from linkage
equilibrium is the difference in these two quantities, D,
D=P.sub.11-p.sub.1q.sub.1 (16)
D=0 indicates perfect linkage equilibrium. Substantial departures
from D=0 indicates LD in the sample of chromosomes examined. Many
properties of D are discussed in Lewontin (1964) including the
maximum and minimum values that D can take. Mathematically, using
basic algebra, it can be shown that D can also be written solely in
terms of haplotypes:
D=P.sub.11P.sub.22-P.sub.12P.sub.21 (17)
If one transforms D by squaring it and subsequently dividing by the
product of the allele frequencies of A.sub.1, A.sub.2, B.sub.1 and
B.sub.2, the resulting quantity, called r.sup.2, is equivalent to
the square of the Pearson's correlation coefficient commonly used
in statistics (e.g. Hoel, 1954).
r 2 = D 2 p 1 p 2 q 1 q 2 ( 18 ) ##EQU00001##
[0305] As with D, values of r.sup.2 close to 0 indicate linkage
equilibrium between the two markers examined in the sample set. As
values of r.sup.2 increase, the two markers are said to be in
linkage disequilibrium. The range of values that r.sup.2 can take
are from 0 to 1. r.sup.2=1 when there is a perfect correlation
between the alleles at the two markers.
[0306] In addition, the quantities discussed above are
sample-specific. And as such, it is necessary to formulate notation
specific to the samples studied. In the approach discussed here,
three types of samples are of primary interest: (i) a sample of
chromosomes from individuals affected by a disease-related
phenotype (cases), (ii) a sample of chromosomes obtained from
individuals not affected by the disease-related phenotype
(controls), and (iii) a standard sample set used for the
construction of haplotypes and calculation pairwise linkage
disequilibrium. For the allele frequencies used in the development
of the method described below, an additional subscript will be
added to denote either the case or control sample sets.
P.sub.1,cs=freq(A.sub.1 in cases) (19)
P.sub.2,cs=freq(A.sub.2 in cases) (20)
q.sub.1,cs=freq(B.sub.1 in cases) (21)
q.sub.2,cs=freq(B.sub.2 in cases) (22)
Similarly,
p.sub.1,ct=freq(A.sub.1 in controls) (23)
p.sub.2,ct=freq(A.sub.2 in controls) (24)
q.sub.1,ct=freq(B.sub.1 in controls) (25)
q.sub.2,ct=freq(B.sub.2 in controls) (26)
[0307] As a well-accepted sample set is necessary for robust
linkage disequilibrium calculations, data obtained from the
International HapMap project (The International HapMap Consortium
2003, 2005; Thorisson et al, 2005; McVean et al, 2005) can be used
for the calculation of pairwise r.sup.2 values. Indeed, the samples
genotyped for the International HapMap Project were selected to be
representative examples from various human sub-populations with
sufficient numbers of chromosomes examined to draw meaningful and
robust conclusions from the patterns of genetic variation observed.
The International HapMap project website (hapmap.org) contains a
description of the project, methods utilized and samples examined.
It is useful to examine empirical data to get a sense of the
patterns present in such data.
[0308] Haplotype frequencies were explicit arguments in equation
(18) above. However, knowing the 2-marker haplotype frequencies
requires that phase to be determined for doubly heterozygous
samples. When phase is unknown in the data examined, various
algorithms can be used to infer phase from the genotype data. This
issue was discussed earlier where the doubly heterozygous
individual with a 2-SNP genotype of A.sub.1A.sub.2B.sub.1B.sub.2
could have one of two different sets of chromosomes:
A.sub.1B.sub.1/A.sub.2B.sub.2 or B.sub.2/A.sub.2B.sub.1. One such
algorithm to estimate haplotype frequencies is the
expectation-maximization (EM) algorithm first formalized by
Dempster et al. (1977). This algorithm is often used in genetics to
infer haplotype frequencies from genotype data (e.g. Excoffier and
Slatkin (1995); Tregouet et al. (2004)). It should be noted that
for the two-SNP case explored here, EM algorithms have very little
error provided that the allele frequencies and sample sizes are not
too small. The impact on r.sup.2 values is typically
negligible.
[0309] As correlated genetic markers share information,
interrogation of SNP markers in LD with a disease-associated SNP
marker can also have sufficient power to detect disease association
(Long and Langley (1999)). The relationship between the power to
directly find disease-associated alleles and the power to
indirectly detect disease-association was investigated by Pritchard
and Przeworski (2001). In a straight-forward derivation, it can be
shown that the power to detect disease association indirectly at a
marker locus in linkage disequilibrium with a disease-association
locus is approximately the same as the power to detect
disease-association directly at the disease-association locus if
the sample size is increased by a factor of
1 r 2 ##EQU00002##
(the reciprocal of equation 18) at the marker in comparison with
the disease-association locus.
[0310] Therefore, if one calculated the power to detect
disease-association indirectly with an experiment having N samples,
then equivalent power to directly detect disease-association (at
the actual disease-susceptibility locus) would necessitate an
experiment using approximately r.sup.2N samples. This elementary
relationship between power, sample size and linkage disequilibrium
can be used to derive an r.sup.2 threshold value useful in
determining whether or not genotyping markers in linkage
disequilibrium with a SNP marker directly associated with disease
status has enough power to indirectly detect
disease-association.
[0311] To commence a derivation of the power to detect
disease-associated markers through an indirect process, define the
effective chromosomal sample size as
n = 4 N cs N ct N cs + N ct ; ( 27 ) ##EQU00003##
where N.sub.cs and N.sub.ct are the numbers of diploid cases and
controls, respectively. This is necessary to handle situations
where the numbers of cases and controls are not equivalent. For
equal case and control sample sizes, N.sub.cs=N.sub.ct=N, the value
of the effective number of chromosomes is simply n=2N--as expected.
Let power be calculated for a significance level a (such that
traditional P-values below .alpha. will be deemed statistically
significant). Define the standard Gaussian distribution function as
.PHI.(.cndot.). Mathematically,
.PHI. ( x ) = 1 2 .pi. .intg. - .infin. x - .theta. 2 2 .theta. (
28 ) ##EQU00004##
Alternatively, the following error function notation (Erf) may also
be used,
.PHI. ( x ) = 1 2 [ 1 + Erf ( x 2 ) ] ( 29 ) ##EQU00005##
[0312] For example, .PHI.(1.644854)=0.95. The value of r.sup.2 may
be derived to yield a pre-specified minimum amount of power to
detect disease association though indirect interrogation. Noting
that the LD SNP marker could be the one that is carrying the
disease-association allele, therefore that this approach
constitutes a lower-bound model where all indirect power results
are expected to be at least as large as those interrogated.
[0313] Denote by .beta. the error rate for not detecting truly
disease-associated markers. Therefore, 1-.beta. is the classical
definition of statistical power. Substituting the
Pritchard-Pzreworski result into the sample size, the power to
detect disease association at a significance level of .alpha. is
given by the approximation
1 - .beta. .apprxeq. .PHI. [ q 1 , cs - q 1 , ct q 1 , cs ( 1 - q 1
, cs ) + q 1 , ct ( 1 - q 1 , ct ) r 2 n - Z 1 - .alpha. / 2 ] ; (
30 ) ##EQU00006##
where Z.sub.u is the inverse of the standard normal cumulative
distribution evaluated at u (u.epsilon.(0,1)). Z.sub.u=.PHI..sup.-1
(u), where .PHI.(.PHI..sup.-1(u))=.PHI..sup.-1(.PHI.(u))=u. For
example, setting .alpha.=0.05, and therefore 1-.alpha./2=0.975, one
obtains Z.sub.0.975=1.95996. Next, setting power equal to a
threshold of a minimum power of T,
T = .PHI. [ q 1 , cs - q 1 , ct q 1 , cs ( 1 - q 1 , cs ) + q 1 ,
ct ( 1 - q 1 , ct ) r 2 n - Z 1 - .alpha. / 2 ] ( 31 )
##EQU00007##
and solving for r.sup.2, the following threshold r.sup.2 is
obtained:
r T 2 = [ q 1 , cs ( 1 - q 1 , cs ) + q 1 , ct ( 1 - q 1 , ct ) ] n
( q 1 , cs - q 1 , ct ) 2 [ .PHI. - 1 ( T ) + Z 1 - .alpha. / 2 ] 2
( 32 ) ##EQU00008##
Or,
[0314] r T 2 = ( Z T + Z 1 - .alpha. / 2 ) 2 n [ q 1 , cs - ( q 1 ,
cs ) 2 + q 1 , ct - ( q 1 , ct ) 2 ( q 1 , cs - q 1 , ct ) 2 ] ( 33
) ##EQU00009##
[0315] Suppose that r.sup.2 is calculated between an interrogated
SNP and a number of other SNPs with varying levels of LD with the
interrogated SNP. The threshold value r.sub.T.sup.2 is the minimum
value of linkage disequilibrium between the interrogated SNP and
the potential LD SNPs such that the LD SNP still retains a power
greater or equal to T for detecting disease-association. For
example, suppose that SNP rs200 is genotyped in a case-control
disease-association study and it is found to be associated with a
disease phenotype. Further suppose that the minor allele frequency
in 1,000 case chromosomes was found to be 16% in contrast with a
minor allele frequency of 10% in 1,000 control chromosomes. Given
those measurements one could have predicted, prior to the
experiment, that the power to detect disease association at a
significance level of 0.05 was quite high--approximately 98% using
a test of allelic association. Applying equation (32) one can
calculate a minimum value of r.sup.2 to indirectly assess disease
association assuming that the minor allele at SNP rs200 is truly
disease-predisposing for a threshold level of power. If one sets
the threshold level of power to be 80%, then r.sub.T.sup.2=0.489
given the same significance level and chromosome numbers as above.
Hence, any SNP with a pairwise r.sup.2 value with rs200 greater
than 0.489 is expected to have greater than 80% power to detect the
disease association. Further, this is assuming the conservative
model where the LD SNP is disease-associated only through linkage
disequilibrium with the interrogated SNP rs200.
[0316] Imputation
[0317] Genotypes of SNPs can be imputed without actually having to
be directly genotyped (referred to as "imputation"), such as by
using known haplotype information. Imputation is particularly
useful for identifying disease associations for specific known but
ungenotyped SNPs by imputing missing genotypes to these ungenotyped
SNPs. Haplotype information (such as from the HapMap project by The
International HapMap Consortium) can be used to infer haplotype
phase and/or impute genotypes for known SNPs that are not directly
genotyped in a given individual or sample set (such as for a
disease association study). In general, imputation is based on
using a reference dataset in which the genotypes of potential SNPs
that are to be tested for disease association have been determined
in multiple individuals (such as in HapMap), and then applying this
reference dataset to infer haplotype phase and/or impute missing
genotypes in additional individuals or samples for SNPs that have
not been directly genotyped. The HapMap dataset is particularly
useful as the reference dataset, however other datasets can be
used. Haplotype phase can be determined based on LD and, since
haplotypes can be correlated with other SNPs within a genomic
region due to LD, ungenotyped SNPs can be tested for disease
associations (or other traits) by testing haplotypes or by imputing
genotypes to the ungenotyped SNPs. The majority of methods used for
haplotype phase inference can also be used to impute missing
genotypes, however methods for imputing missing genotypes do not
necessarily rely on haplotype phase inference (Browning, Hum Genet
(2008) 124:439-450). Certain exemplary methods for haplotype phase
inference and imputation of missing genotypes utilize the BEAGLE
genetic analysis program.
[0318] Thus, SNPs for which genotypes are imputed can be tested for
association with a disease or other trait even though these SNPs
are not directly genotyped. The SNPs for which genotypes are
imputed can be, for example, SNPs that have genotype data available
in HapMap but that are not directly genotyped in a particular
individual or sample set (such as in a particularly disease
association study).
[0319] In addition to using a reference dataset (e.g., HapMap) to
impute genotypes of SNPs that are not directly genotyped in a
study, imputation can also be used to impute genotypes of SNPs that
were directly genotyped in a study but for which the genotypes are
missing for some reason such as because they failed to pass quality
control, and imputation can also be used to combine genotyping
results from multiple studies in which different sets of SNPs were
genotyped. For example, genotyping results from multiple different
studies can be combined, and genotypes can be imputed for SNPs that
have been genotyped in some, but not all, of the studies (Browning,
Hum Genet (2008) 124:439-450).
[0320] For a review of imputation (as well as the BEAGLE program),
see Browning, "Missing data imputation and haplotype phase
inference for genome-wide association studies", Hum Genet (2008)
124:439-450, incorporated herein by reference.
[0321] The contribution or association of particular SNPs and/or
SNP haplotypes with disease phenotypes, such as psoriasis, enables
the SNPs of the present invention to be used to develop superior
diagnostic tests capable of identifying individuals who express a
detectable trait, such as psoriasis, as the result of a specific
genotype, or individuals whose genotype places them at an increased
or decreased risk of developing a detectable trait at a subsequent
time as compared to individuals who do not have that genotype. As
described herein, diagnostics may be based on a single SNP or a
group of SNPs. Combined detection of a plurality of SNPs (for
example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 24, 25, 30, 32, 48, 50, 64, 96, 100, or any other
number in-between, or more, of the SNPs provided in Table 1 and/or
Table 2) typically increases the probability of an accurate
diagnosis. For example, the presence of a single SNP known to
correlate with psoriasis might indicate a probability of 20% that
an individual has or is at risk of developing psoriasis, whereas
detection of five SNPs, each of which correlates with psoriasis,
might indicate a probability of 80% that an individual has or is at
risk of developing psoriasis. To further increase the accuracy of
diagnosis or predisposition screening, analysis of the SNPs of the
present invention can be combined with that of other polymorphisms
or other risk factors of psoriasis, such as disease symptoms,
pathological characteristics, family history, diet, environmental
factors or lifestyle factors.
[0322] It will be understood by practitioners skilled in the
treatment or diagnosis of psoriasis that the present invention
generally does not intend to provide an absolute identification of
individuals who are at risk (or less at risk) of developing
psoriasis, and/or pathologies related to psoriasis, but rather to
indicate a certain increased (or decreased) degree or likelihood of
developing the disease based on statistically significant
association results. However, this information is extremely
valuable as it can be used to, for example, initiate preventive
treatments or to allow an individual carrying one or more
significant SNPs or SNP haplotypes to foresee warning signs such as
minor clinical symptoms, or to have regularly scheduled physical
exams to monitor for appearance of a condition in order to identify
and begin treatment of the condition at an early stage.
Particularly with diseases that are extremely debilitating or fatal
if not treated on time, the knowledge of a potential
predisposition, even if this predisposition is not absolute, would
likely contribute in a very significant manner to treatment
efficacy.
[0323] The diagnostic techniques of the present invention may
employ a variety of methodologies to determine whether a test
subject has a SNP or a SNP pattern associated with an increased or
decreased risk of developing a detectable trait or whether the
individual suffers from a detectable trait as a result of a
particular polymorphism/mutation, including, for example, methods
which enable the analysis of individual chromosomes for
haplotyping, family studies, single sperm DNA analysis, or somatic
hybrids. The trait analyzed using the diagnostics of the invention
may be any detectable trait that is commonly observed in
pathologies and disorders related to psoriasis.
[0324] Another aspect of the present invention relates to a method
of determining whether an individual is at risk (or less at risk)
of developing one or more traits or whether an individual expresses
one or more traits as a consequence of possessing a particular
trait-causing or trait-influencing allele. These methods generally
involve obtaining a nucleic acid sample from an individual and
assaying the nucleic acid sample to determine which nucleotide(s)
is/are present at one or more SNP positions, wherein the assayed
nucleotide(s) is/are indicative of an increased or decreased risk
of developing the trait or indicative that the individual expresses
the trait as a result of possessing a particular trait-causing or
trait-influencing allele.
[0325] In another embodiment, the SNP detection reagents of the
present invention are used to determine whether an individual has
one or more SNP allele(s) affecting the level (e.g., the
concentration of mRNA or protein in a sample, etc.) or pattern
(e.g., the kinetics of expression, rate of decomposition, stability
profile, Km, Vmax, etc.) of gene expression (collectively, the
"gene response" of a cell or bodily fluid). Such a determination
can be accomplished by screening for mRNA or protein expression
(e.g., by using nucleic acid arrays, RT-PCR, TaqMan assays, or mass
spectrometry), identifying genes having altered expression in an
individual, genotyping SNPs disclosed in Table 1 and/or Table 2
that could affect the expression of the genes having altered
expression (e.g., SNPs that are in and/or around the gene(s) having
altered expression, SNPs in regulatory/control regions, SNPs in
and/or around other genes that are involved in pathways that could
affect the expression of the gene(s) having altered expression, or
all SNPs could be genotyped), and correlating SNP genotypes with
altered gene expression. In this manner, specific SNP alleles at
particular SNP sites can be identified that affect gene
expression.
[0326] Therapeutics, Pharmacogenomics, and Drug Development
[0327] Therapeutic Methods and Compositions
[0328] In certain aspects of the invention, there are provided
methods of assaying (i.e., testing) one or more SNPs provided by
the present invention in an individual's nucleic acids, and
administering a therapeutic or preventive agent to the individual
based on the allele(s) present at the SNP(s) having indicated that
the individual can benefit from the therapeutic or preventive
agent.
[0329] In further aspects of the invention, there are provided
methods of assaying one or more SNPs provided by the present
invention in an individual's nucleic acids, and administering a
diagnostic agent (e.g., an imaging agent), or otherwise carrying
out further diagnostic procedures on the individual, based on the
allele(s) present at the SNP(s) having indicated that the
diagnostic agents or diagnostics procedures are justified in the
individual.
[0330] In yet other aspects of the invention, there is provided a
pharmaceutical pack comprising a therapeutic agent (e.g., a small
molecule drug, antibody, peptide, antisense or RNAi nucleic acid
molecule, etc.) and a set of instructions for administration of the
therapeutic agent to an individual who has been tested for one or
more SNPs provided by the present invention.
[0331] Pharmacogenomics
[0332] The present invention provides methods for assessing the
pharmacogenomics of a subject harboring particular SNP alleles or
haplotypes to a particular therapeutic agent or pharmaceutical
compound, or to a class of such compounds. Pharmacogenomics deals
with the roles which clinically significant hereditary variations
(e.g., SNPs) play in the response to drugs due to altered drug
disposition and/or abnormal action in affected persons. See, e.g.,
Roses, Nature 405, 857-865 (2000); Gould Rothberg, Nature
Biotechnology 19, 209-211 (2001); Eichelbaum, Clin Exp Pharmacol
Physiol 23(10-11):983-985 (1996); and Linder, Clin Chem
43(2):254-266 (1997). The clinical outcomes of these variations can
result in severe toxicity of therapeutic drugs in certain
individuals or therapeutic failure of drugs in certain individuals
as a result of individual variation in metabolism. Thus, the SNP
genotype of an individual can determine the way a therapeutic
compound acts on the body or the way the body metabolizes the
compound. For example, SNPs in drug metabolizing enzymes can affect
the activity of these enzymes, which in turn can affect both the
intensity and duration of drug action, as well as drug metabolism
and clearance.
[0333] The discovery of SNPs in drug metabolizing enzymes, drug
transporters, proteins for pharmaceutical agents, and other drug
targets has explained why some patients do not obtain the expected
drug effects, show an exaggerated drug effect, or experience
serious toxicity from standard drug dosages. SNPs can be expressed
in the phenotype of the extensive metabolizer and in the phenotype
of the poor metabolizer. Accordingly, SNPs may lead to allelic
variants of a protein in which one or more of the protein functions
in one population are different from those in another population.
SNPs and the encoded variant peptides thus provide targets to
ascertain a genetic predisposition that can affect treatment
modality. For example, in a ligand-based treatment, SNPs may give
rise to amino terminal extracellular domains and/or other
ligand-binding regions of a receptor that are more or less active
in ligand binding, thereby affecting subsequent protein activation.
Accordingly, ligand dosage would necessarily be modified to
maximize the therapeutic effect within a given population
containing particular SNP alleles or haplotypes.
[0334] As an alternative to genotyping, specific variant proteins
containing variant amino acid sequences encoded by alternative SNP
alleles could be identified. Thus, pharmacogenomic characterization
of an individual permits the selection of effective compounds and
effective dosages of such compounds for prophylactic or therapeutic
uses based on the individual's SNP genotype, thereby enhancing and
optimizing the effectiveness of the therapy. Furthermore, the
production of recombinant cells and transgenic animals containing
particular SNPs/haplotypes allow effective clinical design and
testing of treatment compounds and dosage regimens. For example,
transgenic animals can be produced that differ only in specific SNP
alleles in a gene that is orthologous to a human disease
susceptibility gene.
[0335] Pharmacogenomic uses of the SNPs of the present invention
provide several significant advantages for patient care,
particularly in predicting an individual's predisposition to
psoriasis and in predicting an individual's responsiveness to a
drug (particularly for treating or preventing psoriasis).
Pharmacogenomic characterization of an individual, based on an
individual's SNP genotype, can identify those individuals unlikely
to respond to treatment with a particular medication and thereby
allows physicians to avoid prescribing the ineffective medication
to those individuals. On the other hand, SNP genotyping of an
individual may enable physicians to select the appropriate
medication and dosage regimen that will be most effective based on
an individual's SNP genotype. This information increases a
physician's confidence in prescribing medications and motivates
patients to comply with their drug regimens. Furthermore,
pharmacogenomics may identify patients predisposed to toxicity and
adverse reactions to particular drugs or drug dosages. Adverse drug
reactions lead to more than 100,000 avoidable deaths per year in
the United States alone and therefore represent a significant cause
of hospitalization and death, as well as a significant economic
burden on the healthcare system (Pfost et al., Trends in
Biotechnology, August 2000.). Thus, pharmacogenomics based on the
SNPs disclosed herein has the potential to both save lives and
reduce healthcare costs substantially.
[0336] Pharmacogenomics in general is discussed further in Rose et
al., "Pharmacogenetic analysis of clinically relevant genetic
polymorphisms," Methods Mol Med 85:225-37 (2003). Pharmacogenomics
as it relates to Alzheimer's disease and other neurodegenerative
disorders is discussed in Cacabelos, "Pharmacogenomics for the
treatment of dementia," Ann Med 34(5):357-79 (2002); Maimone et
al., "Pharmacogenomics of neurodegenerative diseases," Eur J
Pharmacol 413(1):11-29 (February 2001); and Poirier,
"Apolipoprotein E: a pharmacogenetic target for the treatment of
Alzheimer's disease," Mol Diagn 4(4):335-41 (December 1999).
Pharmacogenomics as it relates to cardiovascular disorders is
discussed in Siest et al., "Pharmacogenomics of drugs affecting the
cardiovascular system," Clin Chem Lab Med 41(4):590-9 (April 2003);
Mukherjee et al., "Pharmacogenomics in cardiovascular diseases,"
Prog Cardiovasc Dis 44(6):479-98 (May-June 2002); and Mooser et
al., "Cardiovascular pharmacogenetics in the SNP era," J Thromb
Haemost 1(7):1398-402 (July 2003). Pharmacogenomics as it relates
to cancer is discussed in McLeod et al., "Cancer pharmacogenomics:
SNPs, chips, and the individual patient," Cancer Invest
21(4):630-40 (2003); and Watters et al., "Cancer pharmacogenomics:
current and future applications," Biochim Biophys Acta
1603(2):99-111 (March 2003).
[0337] Clinical Trials
[0338] In certain aspects of the invention, there are provided
methods of using the SNPs disclosed herein to identify or stratify
patient populations for clinical trials of a therapeutic,
preventive, or diagnostic agent.
[0339] For instance, an aspect of the present invention includes
selecting individuals for clinical trials based on their SNP
genotype, such as selecting individuals for inclusion in a clinical
trial and/or assigning individuals to a particular group within a
clinical trial (e.g., an "arm" or "cohort" of the trial). For
example, individuals with SNP genotypes that indicate that they are
likely to positively respond to a drug can be included in the
trials, whereas those individuals whose SNP genotypes indicate that
they are less likely to or would not respond to the drug, or who
are at risk for suffering toxic effects or other adverse reactions,
can be excluded from the clinical trials. This not only can improve
the safety of clinical trials, but also can enhance the chances
that the trial will demonstrate statistically significant
efficacy.
[0340] Thus, certain embodiments of the invention provide methods
for conducting a clinical trial of a therapeutic agent in which a
human is selected for inclusion in the clinical trial and/or
assigned to a particular group within a clinical trial based on the
presence or absence of one or more SNPs disclosed herein. In
certain embodiments, the therapeutic agent is an agent that targets
IL12 and/or IL23, such as an anti-IL12 or anti-IL23 antibody.
[0341] In certain exemplary embodiments, SNPs of the invention can
be used to select individuals who are unlikely to respond
positively to a particular therapeutic agent (or class of
therapeutic agents) based on their SNP genotype(s) to participate
in a clinical trial of another type of drug that may benefit them.
Thus, in certain embodiments, the SNPs of the invention can be used
to identify patient populations who do not adequately respond to
current treatments and are therefore in need of new therapies. This
not only benefits the patients themselves, but also benefits
organizations such as pharmaceutical companies by enabling the
identification of populations that represent markets for new drugs,
and enables the efficacy of these new drugs to be tested during
clinical trials directly in individuals within these markets.
[0342] The SNP-containing nucleic acid molecules of the present
invention are also useful for monitoring the effectiveness of
modulating compounds on the expression or activity of a variant
gene, or encoded product, particularly in a treatment regimen or in
clinical trials. Thus, the gene expression pattern can serve as an
indicator for the continuing effectiveness of treatment with the
compound, particularly with compounds to which a patient can
develop resistance, as well as an indicator for toxicities. The
gene expression pattern can also serve as a marker indicative of a
physiological response of the affected cells to the compound.
Accordingly, such monitoring would allow either increased
administration of the compound or the administration of alternative
compounds to which the patient has not become resistant.
[0343] Furthermore, the SNPs of the present invention may have
utility in determining why certain previously developed drugs
performed poorly in clinical trials and may help identify a subset
of the population that would benefit from a drug that had
previously performed poorly in clinical trials, thereby "rescuing"
previously developed drugs, and enabling the drug to be made
available to a particular psoriasis patient population that can
benefit from it.
[0344] Identification, Screening, and Use of Therapeutic Agents
[0345] The SNPs of the present invention also can be used to
identify novel therapeutic targets for psoriasis. For example,
genes containing the disease-associated variants ("variant genes")
or their products, as well as genes or their products that are
directly or indirectly regulated by or interacting with these
variant genes or their products, can be targeted for the
development of therapeutics that, for example, treat the disease or
prevent or delay disease onset. The therapeutics may be composed
of, for example, small molecules, proteins, protein fragments or
peptides, antibodies, nucleic acids, or their derivatives or
mimetics which modulate the functions or levels of the target genes
or gene products.
[0346] The invention further provides methods for identifying a
compound or agent that can be used to treat psoriasis. The SNPs
disclosed herein are useful as targets for the identification
and/or development of therapeutic agents. A method for identifying
a therapeutic agent or compound typically includes assaying the
ability of the agent or compound to modulate the activity and/or
expression of a SNP-containing nucleic acid or the encoded product
and thus identifying an agent or a compound that can be used to
treat a disorder characterized by undesired activity or expression
of the SNP-containing nucleic acid or the encoded product. The
assays can be performed in cell-based and cell-free systems.
Cell-based assays can include cells naturally expressing the
nucleic acid molecules of interest or recombinant cells genetically
engineered to express certain nucleic acid molecules.
[0347] Variant gene expression in a psoriasis patient can include,
for example, either expression of a SNP-containing nucleic acid
sequence (for instance, a gene that contains a SNP can be
transcribed into an mRNA transcript molecule containing the SNP,
which can in turn be translated into a variant protein) or altered
expression of a normal/wild-type nucleic acid sequence due to one
or more SNPs (for instance, a regulatory/control region can contain
a SNP that affects the level or pattern of expression of a normal
transcript).
[0348] Assays for variant gene expression can involve direct assays
of nucleic acid levels (e.g., mRNA levels), expressed protein
levels, or of collateral compounds involved in a signal pathway.
Further, the expression of genes that are up- or down-regulated in
response to the signal pathway can also be assayed. In this
embodiment, the regulatory regions of these genes can be operably
linked to a reporter gene such as luciferase.
[0349] Modulators of variant gene expression can be identified in a
method wherein, for example, a cell is contacted with a candidate
compound/agent and the expression of mRNA determined. The level of
expression of mRNA in the presence of the candidate compound is
compared to the level of expression of mRNA in the absence of the
candidate compound. The candidate compound can then be identified
as a modulator of variant gene expression based on this comparison
and be used to treat a disorder such as psoriasis that is
characterized by variant gene expression (e.g., either expression
of a SNP-containing nucleic acid or altered expression of a
normal/wild-type nucleic acid molecule due to one or more SNPs that
affect expression of the nucleic acid molecule) due to one or more
SNPs of the present invention. When expression of mRNA is
statistically significantly greater in the presence of the
candidate compound than in its absence, the candidate compound is
identified as a stimulator of nucleic acid expression. When nucleic
acid expression is statistically significantly less in the presence
of the candidate compound than in its absence, the candidate
compound is identified as an inhibitor of nucleic acid
expression.
[0350] The invention further provides methods of treatment, with
the SNP or associated nucleic acid domain (e.g., catalytic domain,
ligand/substrate-binding domain, regulatory/control region, etc.)
or gene, or the encoded mRNA transcript, as a target, using a
compound identified through drug screening as a gene modulator to
modulate variant nucleic acid expression. Modulation can include
either up-regulation (i.e., activation or agonization) or
down-regulation (i.e., suppression or antagonization) of nucleic
acid expression.
[0351] Expression of mRNA transcripts and encoded proteins, either
wild type or variant, may be altered in individuals with a
particular SNP allele in a regulatory/control element, such as a
promoter or transcription factor binding domain, that regulates
expression. In this situation, methods of treatment and compounds
can be identified, as discussed herein, that regulate or overcome
the variant regulatory/control element, thereby generating normal,
or healthy, expression levels of either the wild type or variant
protein.
[0352] Pharmaceutical Compositions and Administration Thereof
[0353] Any of the psoriasis-associated proteins, and encoding
nucleic acid molecules, disclosed herein can be used as therapeutic
targets (or directly used themselves as therapeutic compounds) for
treating or preventing psoriasis or related pathologies, and the
present disclosure enables therapeutic compounds (e.g., small
molecules, antibodies, therapeutic proteins, RNAi and antisense
molecules, etc.) to be developed that target (or are comprised of)
any of these therapeutic targets.
[0354] In general, a therapeutic compound will be administered in a
therapeutically effective amount by any of the accepted modes of
administration for agents that serve similar utilities. The actual
amount of the therapeutic compound of this invention, i.e., the
active ingredient, will depend upon numerous factors such as the
severity of the disease to be treated, the age and relative health
of the subject, the potency of the compound used, the route and
form of administration, and other factors.
[0355] Therapeutically effective amounts of therapeutic compounds
may range from, for example, approximately 0.01-50 mg per kilogram
body weight of the recipient per day; preferably about 0.1-20
mg/kg/day. Thus, as an example, for administration to a 70-kg
person, the dosage range would most preferably be about 7 mg to 1.4
g per day.
[0356] In general, therapeutic compounds will be administered as
pharmaceutical compositions by any one of the following routes:
oral, systemic (e.g., transdermal, intranasal, or by suppository),
or parenteral (e.g., intramuscular, intravenous, or subcutaneous)
administration. The preferred manner of administration is oral or
parenteral using a convenient daily dosage regimen, which can be
adjusted according to the degree of affliction. Oral compositions
can take the form of tablets, pills, capsules, semisolids, powders,
sustained release formulations, solutions, suspensions, elixirs,
aerosols, or any other appropriate compositions.
[0357] The choice of formulation depends on various factors such as
the mode of drug administration (e.g., for oral administration,
formulations in the form of tablets, pills, or capsules are
preferred) and the bioavailability of the drug substance. Recently,
pharmaceutical formulations have been developed especially for
drugs that show poor bioavailability based upon the principle that
bioavailability can be increased by increasing the surface area,
i.e., decreasing particle size. For example, U.S. Pat. No.
4,107,288 describes a pharmaceutical formulation having particles
in the size range from 10 to 1,000 nm in which the active material
is supported on a cross-linked matrix of macromolecules. U.S. Pat.
No. 5,145,684 describes the production of a pharmaceutical
formulation in which the drug substance is pulverized to
nanoparticles (average particle size of 400 nm) in the presence of
a surface modifier and then dispersed in a liquid medium to give a
pharmaceutical formulation that exhibits remarkably high
bioavailability.
[0358] Pharmaceutical compositions are comprised of, in general, a
therapeutic compound in combination with at least one
pharmaceutically acceptable excipient. Acceptable excipients are
non-toxic, aid administration, and do not adversely affect the
therapeutic benefit of the therapeutic compound. Such excipients
may be any solid, liquid, semi-solid or, in the case of an aerosol
composition, gaseous excipient that is generally available to one
skilled in the art.
[0359] Solid pharmaceutical excipients include starch, cellulose,
talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, dried skim milk and the like. Liquid
and semisolid excipients may be selected from glycerol, propylene
glycol, water, ethanol and various oils, including those of
petroleum, animal, vegetable or synthetic origin, e.g., peanut oil,
soybean oil, mineral oil, sesame oil, etc. Preferred liquid
carriers, particularly for injectable solutions, include water,
saline, aqueous dextrose, and glycols.
[0360] Compressed gases may be used to disperse a compound of this
invention in aerosol form. Inert gases suitable for this purpose
are nitrogen, carbon dioxide, etc.
[0361] Other suitable pharmaceutical excipients and their
formulations are described in Remington's Pharmaceutical Sciences
18.sup.th ed., E. W. Martin, ed., Mack Publishing Company
(1990).
[0362] The amount of the therapeutic compound in a formulation can
vary within the full range employed by those skilled in the art.
Typically, the formulation will contain, on a weight percent (wt %)
basis, from about 0.01-99.99 wt % of the therapeutic compound based
on the total formulation, with the balance being one or more
suitable pharmaceutical excipients. Preferably, the compound is
present at a level of about 1-80% wt.
[0363] Therapeutic compounds can be administered alone or in
combination with other therapeutic compounds or in combination with
one or more other active ingredient(s). For example, an inhibitor
or stimulator of a psoriasis-associated protein can be administered
in combination with another agent that inhibits or stimulates the
activity of the same or a different psoriasis-associated protein to
thereby counteract the effects of psoriasis.
[0364] For further information regarding pharmacology, see Current
Protocols in Pharmacology, John Wiley & Sons, Inc., N.Y.
[0365] Nucleic Acid-Based Therapeutic Agents
[0366] The SNP-containing nucleic acid molecules disclosed herein,
and their complementary nucleic acid molecules, may be used as
antisense constructs to control gene expression in cells, tissues,
and organisms. Antisense technology is well established in the art
and extensively reviewed in Antisense Drug Technology: Principles,
Strategies, and Applications, Crooke, ed., Marcel Dekker, Inc.,
N.Y. (2001). An antisense nucleic acid molecule is generally
designed to be complementary to a region of mRNA expressed by a
gene so that the antisense molecule hybridizes to the mRNA and
thereby blocks translation of mRNA into protein. Various classes of
antisense oligonucleotides are used in the art, two of which are
cleavers and blockers. Cleavers, by binding to target RNAs,
activate intracellular nucleases (e.g., RNaseH or RNase L) that
cleave the target RNA. Blockers, which also bind to target RNAs,
inhibit protein translation through steric hindrance of ribosomes.
Exemplary blockers include peptide nucleic acids, morpholinos,
locked nucleic acids, and methylphosphonates. See, e.g., Thompson,
Drug Discovery Today 7(17): 912-917 (2002). Antisense
oligonucleotides are directly useful as therapeutic agents, and are
also useful for determining and validating gene function (e.g., in
gene knock-out or knock-down experiments).
[0367] Antisense technology is further reviewed in: Lavery et al.,
"Antisense and RNAi: powerful tools in drug target discovery and
validation," Curr Opin Drug Discov Devel 6(4):561-9 (July 2003);
Stephens et al., "Antisense oligonucleotide therapy in cancer,"
Curr Opin Mol Ther 5(2):118-22 (April 2003); Kurreck, "Antisense
technologies. Improvement through novel chemical modifications,"
Eur J Biochem 270(8):1628-44 (April 2003); Dias et al., "Antisense
oligonucleotides: basic concepts and mechanisms," Mol Cancer Ther
1(5):347-55 (March 2002); Chen, "Clinical development of antisense
oligonucleotides as anti-cancer therapeutics," Methods Mol Med
75:621-36 (2003); Wang et al., "Antisense anticancer
oligonucleotide therapeutics," Curr Cancer Drug Targets 1(3):177-96
(November 2001); and Bennett, "Efficiency of antisense
oligonucleotide drug discovery," Antisense Nucleic Acid Drug Dev
12(3):215-24 (June 2002).
[0368] The SNPs of the present invention are particularly useful
for designing antisense reagents that are specific for particular
nucleic acid variants. Based on the SNP information disclosed
herein, antisense oligonucleotides can be produced that
specifically target mRNA molecules that contain one or more
particular SNP nucleotides. In this manner, expression of mRNA
molecules that contain one or more undesired polymorphisms (e.g.,
SNP nucleotides that lead to a defective protein such as an amino
acid substitution in a catalytic domain) can be inhibited or
completely blocked. Thus, antisense oligonucleotides can be used to
specifically bind a particular polymorphic form (e.g., a SNP allele
that encodes a defective protein), thereby inhibiting translation
of this form, but which do not bind an alternative polymorphic form
(e.g., an alternative SNP nucleotide that encodes a protein having
normal function).
[0369] Antisense molecules can be used to inactivate mRNA in order
to inhibit gene expression and production of defective proteins.
Accordingly, these molecules can be used to treat a disorder, such
as psoriasis, characterized by abnormal or undesired gene
expression or expression of certain defective proteins. This
technique can involve cleavage by means of ribozymes containing
nucleotide sequences complementary to one or more regions in the
mRNA that attenuate the ability of the mRNA to be translated.
Possible mRNA regions include, for example, protein-coding regions
and particularly protein-coding regions corresponding to catalytic
activities, substrate/ligand binding, or other functional
activities of a protein.
[0370] The SNPs of the present invention are also useful for
designing RNA interference reagents that specifically target
nucleic acid molecules having particular SNP variants. RNA
interference (RNAi), also referred to as gene silencing, is based
on using double-stranded RNA (dsRNA) molecules to turn genes off.
When introduced into a cell, dsRNAs are processed by the cell into
short fragments (generally about 21, 22, or 23 nucleotides in
length) known as small interfering RNAs (siRNAs) which the cell
uses in a sequence-specific manner to recognize and destroy
complementary RNAs. Thompson, Drug Discovery Today 7(17): 912-917
(2002). Accordingly, an aspect of the present invention
specifically contemplates isolated nucleic acid molecules that are
about 18-26 nucleotides in length, preferably 19-25 nucleotides in
length, and more preferably 20, 21, 22, or 23 nucleotides in
length, and the use of these nucleic acid molecules for RNAi.
Because RNAi molecules, including siRNAs, act in a
sequence-specific manner, the SNPs of the present invention can be
used to design RNAi reagents that recognize and destroy nucleic
acid molecules having specific SNP alleles/nucleotides (such as
deleterious alleles that lead to the production of defective
proteins), while not affecting nucleic acid molecules having
alternative SNP alleles (such as alleles that encode proteins
having normal function). As with antisense reagents, RNAi reagents
may be directly useful as therapeutic agents (e.g., for turning off
defective, disease-causing genes), and are also useful for
characterizing and validating gene function (e.g., in gene
knock-out or knock-down experiments).
[0371] The following references provide a further review of RNAi:
Reynolds et al., "Rational siRNA design for RNA interference," Nat
Biotechnol 22(3):326-30 (March 2004); Epub Feb. 1, 2004; Chi et
al., "Genomewide view of gene silencing by small interfering RNAs,"
PNAS 100(11):6343-6346 (2003); Vickers et al., "Efficient Reduction
of Target RNAs by Small Interfering RNA and RNase H-dependent
Antisense Agents," J Biol Chem 278:7108-7118 (2003); Agami, "RNAi
and related mechanisms and their potential use for therapy," Curr
Opin Chem Biol 6(6):829-34 (December 2002); Lavery et al.,
"Antisense and RNAi: powerful tools in drug target discovery and
validation," Curr Opin Drug Discov Devel 6(4):561-9 (July 2003);
Shi, "Mammalian RNAi for the masses," Trends Genet 19(1):9-12
(January 2003); Shuey et al., "RNAi: gene-silencing in therapeutic
intervention," Drug Discovery Today 7(20):1040-1046 (October 2002);
McManus et al., Nat Rev Genet 3(10):737-47 (October 2002); Xia et
al., Nat Biotechnol 20(10):1006-10 (October 2002); Plasterk et al.,
Curr Opin Genet Dev 10(5):562-7 (October 2000); Bosher et al., Nat
Cell Biol 2(2):E31-6 (February 2000); and Hunter, Curr Biol 17;
9(12):R440-2 (June 1999).
[0372] Other Therapeutic Aspects
[0373] SNPs have many important uses in drug discovery, screening,
and development, and thus the SNPs of the present invention are
useful for improving many different aspects of the drug development
process.
[0374] For example, a high probability exists that, for any
gene/protein selected as a potential drug target, variants of that
gene/protein will exist in a patient population. Thus, determining
the impact of gene/protein variants on the selection and delivery
of a therapeutic agent should be an integral aspect of the drug
discovery and development process. Jazwinska, A Trends Guide to
Genetic Variation and Genomic Medicine S30-S36 (March 2002).
[0375] Knowledge of variants (e.g., SNPs and any corresponding
amino acid polymorphisms) of a particular therapeutic target (e.g.,
a gene, mRNA transcript, or protein) enables parallel screening of
the variants in order to identify therapeutic candidates (e.g.,
small molecule compounds, antibodies, antisense or RNAi nucleic
acid compounds, etc.) that demonstrate efficacy across variants.
Rothberg, Nat Biotechnol 19(3):209-11 (March 2001). Such
therapeutic candidates would be expected to show equal efficacy
across a larger segment of the patient population, thereby leading
to a larger potential market for the therapeutic candidate.
[0376] Furthermore, identifying variants of a potential therapeutic
target enables the most common form of the target to be used for
selection of therapeutic candidates, thereby helping to ensure that
the experimental activity that is observed for the selected
candidates reflects the real activity expected in the largest
proportion of a patient population. Jazwinska, A Trends Guide to
Genetic Variation and Genomic Medicine S30-S36 (March 2002).
[0377] Additionally, screening therapeutic candidates against all
known variants of a target can enable the early identification of
potential toxicities and adverse reactions relating to particular
variants. For example, variability in drug absorption,
distribution, metabolism and excretion (ADME) caused by, for
example, SNPs in therapeutic targets or drug metabolizing genes,
can be identified, and this information can be utilized during the
drug development process to minimize variability in drug
disposition and develop therapeutic agents that are safer across a
wider range of a patient population. The SNPs of the present
invention, including the variant proteins and encoding polymorphic
nucleic acid molecules provided in Tables 1 and 2, are useful in
conjunction with a variety of toxicology methods established in the
art, such as those set forth in Current Protocols in Toxicology,
John Wiley & Sons, Inc., N.Y.
[0378] Furthermore, therapeutic agents that target any art-known
proteins (or nucleic acid molecules, either RNA or DNA) may
cross-react with the variant proteins (or polymorphic nucleic acid
molecules) disclosed in Table 1, thereby significantly affecting
the pharmacokinetic properties of the drug. Consequently, the
protein variants and the SNP-containing nucleic acid molecules
disclosed in Tables 1 and 2 are useful in developing, screening,
and evaluating therapeutic agents that target corresponding
art-known protein forms (or nucleic acid molecules). Additionally,
as discussed above, knowledge of all polymorphic forms of a
particular drug target enables the design of therapeutic agents
that are effective against most or all such polymorphic forms of
the drug target.
[0379] A subject suffering from a pathological condition ascribed
to a SNP, such as psoriasis, may be treated so as to correct the
genetic defect. See Kren et al., Proc Natl Acad Sci USA
96:10349-10354 (1999). Such a subject can be identified by any
method that can detect the polymorphism in a biological sample
drawn from the subject. Such a genetic defect may be permanently
corrected by administering to such a subject a nucleic acid
fragment incorporating a repair sequence that supplies the
normal/wild-type nucleotide at the position of the SNP. This
site-specific repair sequence can encompass an RNA/DNA
oligonucleotide that operates to promote endogenous repair of a
subject's genomic DNA. The site-specific repair sequence is
administered in an appropriate vehicle, such as a complex with
polyethylenimine, encapsulated in anionic liposomes, a viral vector
such as an adenovirus, or other pharmaceutical composition that
promotes intracellular uptake of the administered nucleic acid. A
genetic defect leading to an inborn pathology may then be overcome,
as the chimeric oligonucleotides induce incorporation of the normal
sequence into the subject's genome. Upon incorporation, the normal
gene product is expressed, and the replacement is propagated,
thereby engendering a permanent repair and therapeutic enhancement
of the clinical condition of the subject.
[0380] In cases in which a cSNP results in a variant protein that
is ascribed to be the cause of, or a contributing factor to, a
pathological condition, a method of treating such a condition can
include administering to a subject experiencing the pathology the
wild-type/normal cognate of the variant protein. Once administered
in an effective dosing regimen, the wild-type cognate provides
complementation or remediation of the pathological condition.
[0381] Human Identification Applications
[0382] In addition to their diagnostic, therapeutic, and preventive
uses in psoriasis and related pathologies, the SNPs provided by the
present invention are also useful as human identification markers
for such applications as forensics, paternity testing, and
biometrics. See, e.g., Gill, "An assessment of the utility of
single nucleotide polymorphisms (SNPs) for forensic purposes," Int
J Legal Med 114(4-5):204-10 (2001). Genetic variations in the
nucleic acid sequences between individuals can be used as genetic
markers to identify individuals and to associate a biological
sample with an individual. Determination of which nucleotides
occupy a set of SNP positions in an individual identifies a set of
SNP markers that distinguishes the individual. The more SNP
positions that are analyzed, the lower the probability that the set
of SNPs in one individual is the same as that in an unrelated
individual. Preferably, if multiple sites are analyzed, the sites
are unlinked (i.e., inherited independently). Thus, preferred sets
of SNPs can be selected from among the SNPs disclosed herein, which
may include SNPs on different chromosomes, SNPs on different
chromosome arms, and/or SNPs that are dispersed over substantial
distances along the same chromosome arm.
[0383] Furthermore, among the SNPs disclosed herein, preferred SNPs
for use in certain forensic/human identification applications
include SNPs located at degenerate codon positions (i.e., the third
position in certain codons which can be one of two or more
alternative nucleotides and still encode the same amino acid),
since these SNPs do not affect the encoded protein. SNPs that do
not affect the encoded protein are expected to be under less
selective pressure and are therefore expected to be more
polymorphic in a population, which is typically an advantage for
forensic/human identification applications. However, for certain
forensics/human identification applications, such as predicting
phenotypic characteristics (e.g., inferring ancestry or inferring
one or more physical characteristics of an individual) from a DNA
sample, it may be desirable to utilize SNPs that affect the encoded
protein.
[0384] For many of the SNPs disclosed in Tables 1 and 2 (which are
identified as "Applera" SNP source), Tables 1 and 2 provide SNP
allele frequencies obtained by re-sequencing the DNA of chromosomes
from 39 individuals (Tables 1 and 2 also provide allele frequency
information for "Celera" source SNPs and, where available, public
SNPs from dbEST, HGBASE, and/or HGMD). The allele frequencies
provided in Tables 1 and 2 enable these SNPs to be readily used for
human identification applications. Although any SNP disclosed in
Table 1 and/or Table 2 could be used for human identification, the
closer that the frequency of the minor allele at a particular SNP
site is to 50%, the greater the ability of that SNP to discriminate
between different individuals in a population since it becomes
increasingly likely that two randomly selected individuals would
have different alleles at that SNP site. Using the SNP allele
frequencies provided in Tables 1 and 2, one of ordinary skill in
the art could readily select a subset of SNPs for which the
frequency of the minor allele is, for example, at least 1%, 2%, 5%,
10%, 20%, 25%, 30%, 40%, 45%, or 50%, or any other frequency
in-between. Thus, since Tables 1 and 2 provide allele frequencies
based on the re-sequencing of the chromosomes from 39 individuals,
a subset of SNPs could readily be selected for human identification
in which the total allele count of the minor allele at a particular
SNP site is, for example, at least 1, 2, 4, 8, 10, 16, 20, 24, 30,
32, 36, 38, 39, 40, or any other number in-between.
[0385] Furthermore, Tables 1 and 2 also provide population group
(interchangeably referred to herein as ethnic or racial groups)
information coupled with the extensive allele frequency
information. For example, the group of 39 individuals whose DNA was
re-sequenced was made-up of 20 Caucasians and 19 African-Americans.
This population group information enables further refinement of SNP
selection for human identification. For example, preferred SNPs for
human identification can be selected from Tables 1 and 2 that have
similar allele frequencies in both the Caucasian and
African-American populations; thus, for example, SNPs can be
selected that have equally high discriminatory power in both
populations. Alternatively, SNPs can be selected for which there is
a statistically significant difference in allele frequencies
between the Caucasian and African-American populations (as an
extreme example, a particular allele may be observed only in either
the Caucasian or the African-American population group but not
observed in the other population group); such SNPs are useful, for
example, for predicting the race/ethnicity of an unknown
perpetrator from a biological sample such as a hair or blood stain
recovered at a crime scene. For a discussion of using SNPs to
predict ancestry from a DNA sample, including statistical methods,
see Frudakis et al., "A Classifier for the SNP-Based Inference of
Ancestry," Journal of Forensic Sciences 48(4):771-782 (2003).
[0386] SNPs have numerous advantages over other types of
polymorphic markers, such as short tandem repeats (STRs). For
example, SNPs can be easily scored and are amenable to automation,
making SNPs the markers of choice for large-scale forensic
databases. SNPs are found in much greater abundance throughout the
genome than repeat polymorphisms. Population frequencies of two
polymorphic forms can usually be determined with greater accuracy
than those of multiple polymorphic forms at multi-allelic loci.
SNPs are mutationally more stable than repeat polymorphisms. SNPs
are not susceptible to artifacts such as stutter bands that can
hinder analysis. Stutter bands are frequently encountered when
analyzing repeat polymorphisms, and are particularly troublesome
when analyzing samples such as crime scene samples that may contain
mixtures of DNA from multiple sources. Another significant
advantage of SNP markers over STR markers is the much shorter
length of nucleic acid needed to score a SNP. For example, STR
markers are generally several hundred base pairs in length. A SNP,
on the other hand, comprises a single nucleotide, and generally a
short conserved region on either side of the SNP position for
primer and/or probe binding. This makes SNPs more amenable to
typing in highly degraded or aged biological samples that are
frequently encountered in forensic casework in which DNA may be
fragmented into short pieces.
[0387] SNPs also are not subject to microvariant and "off-ladder"
alleles frequently encountered when analyzing STR loci.
Microvariants are deletions or insertions within a repeat unit that
change the size of the amplified DNA product so that the amplified
product does not migrate at the same rate as reference alleles with
normal sized repeat units. When separated by size, such as by
electrophoresis on a polyacrylamide gel, microvariants do not align
with a reference allelic ladder of standard sized repeat units, but
rather migrate between the reference alleles. The reference allelic
ladder is used for precise sizing of alleles for allele
classification; therefore alleles that do not align with the
reference allelic ladder lead to substantial analysis problems.
Furthermore, when analyzing multi-allelic repeat polymorphisms,
occasionally an allele is found that consists of more or less
repeat units than has been previously seen in the population, or
more or less repeat alleles than are included in a reference
allelic ladder. These alleles will migrate outside the size range
of known alleles in a reference allelic ladder, and therefore are
referred to as "off-ladder" alleles. In extreme cases, the allele
may contain so few or so many repeats that it migrates well out of
the range of the reference allelic ladder. In this situation, the
allele may not even be observed, or, with multiplex analysis, it
may migrate within or close to the size range for another locus,
further confounding analysis.
[0388] SNP analysis avoids the problems of microvariants and
off-ladder alleles encountered in STR analysis. Importantly,
microvariants and off-ladder alleles may provide significant
problems, and may be completely missed, when using analysis methods
such as oligonucleotide hybridization arrays, which utilize
oligonucleotide probes specific for certain known alleles.
Furthermore, off-ladder alleles and microvariants encountered with
STR analysis, even when correctly typed, may lead to improper
statistical analysis, since their frequencies in the population are
generally unknown or poorly characterized, and therefore the
statistical significance of a matching genotype may be
questionable. All these advantages of SNP analysis are considerable
in light of the consequences of most DNA identification cases,
which may lead to life imprisonment for an individual, or
re-association of remains to the family of a deceased
individual.
[0389] DNA can be isolated from biological samples such as blood,
bone, hair, saliva, or semen, and compared with the DNA from a
reference source at particular SNP positions. Multiple SNP markers
can be assayed simultaneously in order to increase the power of
discrimination and the statistical significance of a matching
genotype. For example, oligonucleotide arrays can be used to
genotype a large number of SNPs simultaneously. The SNPs provided
by the present invention can be assayed in combination with other
polymorphic genetic markers, such as other SNPs known in the art or
STRs, in order to identify an individual or to associate an
individual with a particular biological sample.
[0390] Furthermore, the SNPs provided by the present invention can
be genotyped for inclusion in a database of DNA genotypes, for
example, a criminal DNA databank such as the FBI's Combined DNA
Index System (CODIS) database. A genotype obtained from a
biological sample of unknown source can then be queried against the
database to find a matching genotype, with the SNPs of the present
invention providing nucleotide positions at which to compare the
known and unknown DNA sequences for identity. Accordingly, the
present invention provides a database comprising novel SNPs or SNP
alleles of the present invention (e.g., the database can comprise
information indicating which alleles are possessed by individual
members of a population at one or more novel SNP sites of the
present invention), such as for use in forensics, biometrics, or
other human identification applications. Such a database typically
comprises a computer-based system in which the SNPs or SNP alleles
of the present invention are recorded on a computer readable
medium.
[0391] The SNPs of the present invention can also be assayed for
use in paternity testing. The object of paternity testing is
usually to determine whether a male is the father of a child. In
most cases, the mother of the child is known and thus, the mother's
contribution to the child's genotype can be traced. Paternity
testing investigates whether the part of the child's genotype not
attributable to the mother is consistent with that of the putative
father. Paternity testing can be performed by analyzing sets of
polymorphisms in the putative father and the child, with the SNPs
of the present invention providing nucleotide positions at which to
compare the putative father's and child's DNA sequences for
identity. If the set of polymorphisms in the child attributable to
the father does not match the set of polymorphisms of the putative
father, it can be concluded, barring experimental error, that the
putative father is not the father of the child. If the set of
polymorphisms in the child attributable to the father match the set
of polymorphisms of the putative father, a statistical calculation
can be performed to determine the probability of coincidental
match, and a conclusion drawn as to the likelihood that the
putative father is the true biological father of the child.
[0392] In addition to paternity testing, SNPs are also useful for
other types of kinship testing, such as for verifying familial
relationships for immigration purposes, or for cases in which an
individual alleges to be related to a deceased individual in order
to claim an inheritance from the deceased individual, etc. For
further information regarding the utility of SNPs for paternity
testing and other types of kinship testing, including methods for
statistical analysis, see Krawczak, "Informativity assessment for
biallelic single nucleotide polymorphisms," Electrophoresis
20(8):1676-81 (June 1999).
[0393] The use of the SNPs of the present invention for human
identification further extends to various authentication systems,
commonly referred to as biometric systems, which typically convert
physical characteristics of humans (or other organisms) into
digital data. Biometric systems include various technological
devices that measure such unique anatomical or physiological
characteristics as finger, thumb, or palm prints; hand geometry;
vein patterning on the back of the hand; blood vessel patterning of
the retina and color and texture of the iris; facial
characteristics; voice patterns; signature and typing dynamics; and
DNA. Such physiological measurements can be used to verify identity
and, for example, restrict or allow access based on the
identification. Examples of applications for biometrics include
physical area security, computer and network security, aircraft
passenger check-in and boarding, financial transactions, medical
records access, government benefit distribution, voting, law
enforcement, passports, visas and immigration, prisons, various
military applications, and for restricting access to expensive or
dangerous items, such as automobiles or guns. See, for example,
O'Connor, Stanford Technology Law Review, and U.S. Pat. No.
6,119,096.
[0394] Groups of SNPs, particularly the SNPs provided by the
present invention, can be typed to uniquely identify an individual
for biometric applications such as those described above. Such SNP
typing can readily be accomplished using, for example, DNA
chips/arrays. Preferably, a minimally invasive means for obtaining
a DNA sample is utilized. For example, PCR amplification enables
sufficient quantities of DNA for analysis to be obtained from
buccal swabs or fingerprints, which contain DNA-containing skin
cells and oils that are naturally transferred during contact.
[0395] Further information regarding techniques for using SNPs in
forensic/human identification applications can be found, for
example, in Current Protocols in Human Genetics 14.1-14.7, John
Wiley & Sons, N.Y. (2002).
[0396] Variant Proteins, Antibodies, Vectors, Host Cells, &
Uses Thereof
[0397] Variant Proteins Encoded by SNP-Containing Nucleic Acid
Molecules
[0398] The present invention provides SNP-containing nucleic acid
molecules, many of which encode proteins having variant amino acid
sequences as compared to the art-known (i.e., wild-type) proteins.
Amino acid sequences encoded by the polymorphic nucleic acid
molecules of the present invention are referred to as SEQ ID
NOS:3-4 in Table 1 and provided in the Sequence Listing. These
variants will generally be referred to herein as variant
proteins/peptides/polypeptides, or polymorphic
proteins/peptides/polypeptides of the present invention. The terms
"protein," "peptide," and "polypeptide" are used herein
interchangeably.
[0399] A variant protein of the present invention may be encoded
by, for example, a nonsynonymous nucleotide substitution at any one
of the cSNP positions disclosed herein. In addition, variant
proteins may also include proteins whose expression, structure,
and/or function is altered by a SNP disclosed herein, such as a SNP
that creates or destroys a stop codon, a SNP that affects splicing,
and a SNP in control/regulatory elements, e.g. promoters,
enhancers, or transcription factor binding domains.
[0400] As used herein, a protein or peptide is said to be
"isolated" or "purified" when it is substantially free of cellular
material or chemical precursors or other chemicals. The variant
proteins of the present invention can be purified to homogeneity or
other lower degrees of purity. The level of purification will be
based on the intended use. The key feature is that the preparation
allows for the desired function of the variant protein, even if in
the presence of considerable amounts of other components.
[0401] As used herein, "substantially free of cellular material"
includes preparations of the variant protein having less than about
30% (by dry weight) other proteins (i.e., contaminating protein),
less than about 20% other proteins, less than about 10% other
proteins, or less than about 5% other proteins. When the variant
protein is recombinantly produced, it can also be substantially
free of culture medium, i.e., culture medium represents less than
about 20% of the volume of the protein preparation.
[0402] The language "substantially free of chemical precursors or
other chemicals" includes preparations of the variant protein in
which it is separated from chemical precursors or other chemicals
that are involved in its synthesis. In one embodiment, the language
"substantially free of chemical precursors or other chemicals"
includes preparations of the variant protein having less than about
30% (by dry weight) chemical precursors or other chemicals, less
than about 20% chemical precursors or other chemicals, less than
about 10% chemical precursors or other chemicals, or less than
about 5% chemical precursors or other chemicals.
[0403] An isolated variant protein may be purified from cells that
naturally express it, purified from cells that have been altered to
express it (recombinant host cells), or synthesized using known
protein synthesis methods. For example, a nucleic acid molecule
containing SNP(s) encoding the variant protein can be cloned into
an expression vector, the expression vector introduced into a host
cell, and the variant protein expressed in the host cell. The
variant protein can then be isolated from the cells by any
appropriate purification scheme using standard protein purification
techniques. Examples of these techniques are described in detail
below. Sambrook and Russell, Molecular Cloning: A Laboratory
Manual, Cold Spring Harbor Laboratory Press, N.Y. (2000).
[0404] The present invention provides isolated variant proteins
that comprise, consist of or consist essentially of amino acid
sequences that contain one or more variant amino acids encoded by
one or more codons that contain a SNP of the present invention.
[0405] Accordingly, the present invention provides variant proteins
that consist of amino acid sequences that contain one or more amino
acid polymorphisms (or truncations or extensions due to creation or
destruction of a stop codon, respectively) encoded by the SNPs
provided in Table 1 and/or Table 2. A protein consists of an amino
acid sequence when the amino acid sequence is the entire amino acid
sequence of the protein.
[0406] The present invention further provides variant proteins that
consist essentially of amino acid sequences that contain one or
more amino acid polymorphisms (or truncations or extensions due to
creation or destruction of a stop codon, respectively) encoded by
the SNPs provided in Table 1 and/or Table 2. A protein consists
essentially of an amino acid sequence when such an amino acid
sequence is present with only a few additional amino acid residues
in the final protein.
[0407] The present invention further provides variant proteins that
comprise amino acid sequences that contain one or more amino acid
polymorphisms (or truncations or extensions due to creation or
destruction of a stop codon, respectively) encoded by the SNPs
provided in Table 1 and/or Table 2. A protein comprises an amino
acid sequence when the amino acid sequence is at least part of the
final amino acid sequence of the protein. In such a fashion, the
protein may contain only the variant amino acid sequence or have
additional amino acid residues, such as a contiguous encoded
sequence that is naturally associated with it or heterologous amino
acid residues. Such a protein can have a few additional amino acid
residues or can comprise many more additional amino acids. A brief
description of how various types of these proteins can be made and
isolated is provided below.
[0408] The variant proteins of the present invention can be
attached to heterologous sequences to form chimeric or fusion
proteins. Such chimeric and fusion proteins comprise a variant
protein operatively linked to a heterologous protein having an
amino acid sequence not substantially homologous to the variant
protein. "Operatively linked" indicates that the coding sequences
for the variant protein and the heterologous protein are ligated
in-frame. The heterologous protein can be fused to the N-terminus
or C-terminus of the variant protein. In another embodiment, the
fusion protein is encoded by a fusion polynucleotide that is
synthesized by conventional techniques including automated DNA
synthesizers. Alternatively, PCR amplification of gene fragments
can be carried out using anchor primers which give rise to
complementary overhangs between two consecutive gene fragments
which can subsequently be annealed and re-amplified to generate a
chimeric gene sequence. See Ausubel et al., Current Protocols in
Molecular Biology (1992). Moreover, many expression vectors are
commercially available that already encode a fusion moiety (e.g., a
GST protein). A variant protein-encoding nucleic acid can be cloned
into such an expression vector such that the fusion moiety is
linked in-frame to the variant protein.
[0409] In many uses, the fusion protein does not affect the
activity of the variant protein. The fusion protein can include,
but is not limited to, enzymatic fusion proteins, for example,
beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His
fusions, MYC-tagged, HI-tagged and Ig fusions. Such fusion
proteins, particularly poly-His fusions, can facilitate their
purification following recombinant expression. In certain host
cells (e g, mammalian host cells), expression and/or secretion of a
protein can be increased by using a heterologous signal sequence.
Fusion proteins are further described in, for example, Terpe,
"Overview of tag protein fusions: from molecular and biochemical
fundamentals to commercial systems," Appl Microbiol Biotechnol
60(5):523-33 (January 2003); Epub Nov. 7, 2002; Graddis et al.,
"Designing proteins that work using recombinant technologies," Curr
Pharm Biotechnol 3(4):285-97 (December 2002); and Nilsson et al.,
"Affinity fusion strategies for detection, purification, and
immobilization of recombinant proteins," Protein Expr Purif
11(1):1-16 (October 1997).
[0410] In certain embodiments, novel compositions of the present
invention also relate to further obvious variants of the variant
polypeptides of the present invention, such as naturally-occurring
mature forms (e.g., allelic variants), non-naturally occurring
recombinantly-derived variants, and orthologs and paralogs of such
proteins that share sequence homology. Such variants can readily be
generated using art-known techniques in the fields of recombinant
nucleic acid technology and protein biochemistry.
[0411] Further variants of the variant polypeptides disclosed in
Table 1 can comprise an amino acid sequence that shares at least
70-80%, 80-85%, 85-90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or
99% sequence identity with an amino acid sequence disclosed in
Table 1 (or a fragment thereof) and that includes a novel amino
acid residue (allele) disclosed in Table 1 (which is encoded by a
novel SNP allele). Thus, an aspect of the present invention that is
specifically contemplated are polypeptides that have a certain
degree of sequence variation compared with the polypeptide
sequences shown in Table 1, but that contain a novel amino acid
residue (allele) encoded by a novel SNP allele disclosed herein. In
other words, as long as a polypeptide contains a novel amino acid
residue disclosed herein, other portions of the polypeptide that
flank the novel amino acid residue can vary to some degree from the
polypeptide sequences shown in Table 1.
[0412] Full-length pre-processed forms, as well as mature processed
forms, of proteins that comprise one of the amino acid sequences
disclosed herein can readily be identified as having complete
sequence identity to one of the variant proteins of the present
invention as well as being encoded by the same genetic locus as the
variant proteins provided herein.
[0413] Orthologs of a variant peptide can readily be identified as
having some degree of significant sequence homology/identity to at
least a portion of a variant peptide as well as being encoded by a
gene from another organism. Preferred orthologs will be isolated
from non-human mammals, preferably primates, for the development of
human therapeutic targets and agents. Such orthologs can be encoded
by a nucleic acid sequence that hybridizes to a variant
peptide-encoding nucleic acid molecule under moderate to stringent
conditions depending on the degree of relatedness of the two
organisms yielding the homologous proteins.
[0414] Variant proteins include, but are not limited to, proteins
containing deletions, additions and substitutions in the amino acid
sequence caused by the SNPs of the present invention. One class of
substitutions is conserved amino acid substitutions in which a
given amino acid in a polypeptide is substituted for another amino
acid of like characteristics. Typical conservative substitutions
are replacements, one for another, among the aliphatic amino acids
Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser
and Thr; exchange of the acidic residues Asp and Glu; substitution
between the amide residues Asn and Gln; exchange of the basic
residues Lys and Arg; and replacements among the aromatic residues
Phe and Tyr. Guidance concerning which amino acid changes are
likely to be phenotypically silent are found, for example, in Bowie
et al., Science 247:1306-1310 (1990).
[0415] Variant proteins can be fully functional or can lack
function in one or more activities, e.g. ability to bind another
molecule, ability to catalyze a substrate, ability to mediate
signaling, etc. Fully functional variants typically contain only
conservative variations or variations in non-critical residues or
in non-critical regions. Functional variants can also contain
substitution of similar amino acids that result in no change or an
insignificant change in function. Alternatively, such substitutions
may positively or negatively affect function to some degree.
Non-functional variants typically contain one or more
non-conservative amino acid substitutions, deletions, insertions,
inversions, truncations or extensions, or a substitution,
insertion, inversion, or deletion of a critical residue or in a
critical region.
[0416] Amino acids that are essential for function of a protein can
be identified by methods known in the art, such as site-directed
mutagenesis or alanine-scanning mutagenesis, particularly using the
amino acid sequence and polymorphism information provided in Table
1. Cunningham et al., Science 244:1081-1085 (1989). The latter
procedure introduces single alanine mutations at every residue in
the molecule. The resulting mutant molecules are then tested for
biological activity such as enzyme activity or in assays such as an
in vitro proliferative activity. Sites that are critical for
binding partner/substrate binding can also be determined by
structural analysis such as crystallization, nuclear magnetic
resonance or photoaffinity labeling. Smith et al., J Mol Biol
224:899-904 (1992); de Vos et al., Science 255:306-312 (1992).
[0417] Polypeptides can contain amino acids other than the 20 amino
acids commonly referred to as the 20 naturally occurring amino
acids. Further, many amino acids, including the terminal amino
acids, may be modified by natural processes, such as processing and
other post-translational modifications, or by chemical modification
techniques well known in the art. Accordingly, the variant proteins
of the present invention also encompass derivatives or analogs in
which a substituted amino acid residue is not one encoded by the
genetic code, in which a substituent group is included, in which
the mature polypeptide is fused with another compound, such as a
compound to increase the half-life of the polypeptide (e.g.,
polyethylene glycol), or in which additional amino acids are fused
to the mature polypeptide, such as a leader or secretory sequence
or a sequence for purification of the mature polypeptide or a
pro-protein sequence.
[0418] Known protein modifications include, but are not limited to,
acetylation, acylation, ADP-ribosylation, amidation, covalent
attachment of flavin, covalent attachment of a heme moiety,
covalent attachment of a nucleotide or nucleotide derivative,
covalent attachment of a lipid or lipid derivative, covalent
attachment of phosphotidylinositol, cross-linking, cyclization,
disulfide bond formation, demethylation, formation of covalent
crosslinks, formation of cystine, formation of pyroglutamate,
formylation, gamma carboxylation, glycosylation, GPI anchor
formation, hydroxylation, iodination, methylation, myristoylation,
oxidation, proteolytic processing, phosphorylation, prenylation,
racemization, selenoylation, sulfation, transfer-RNA mediated
addition of amino acids to proteins such as arginylation, and
ubiquitination.
[0419] Such protein modifications are well known to those of skill
in the art and have been described in great detail in the
scientific literature. Particularly common modifications, for
example glycosylation, lipid attachment, sulfation,
gamma-carboxylation of glutamic acid residues, hydroxylation and
ADP-ribosylation, are described in most basic texts, such as
Proteins--Structure and Molecular Properties 2nd Ed., T. E.
Creighton, W.H. Freeman and Company, N.Y. (1993); F. Wold,
Posttranslational Covalent Modification of Proteins 1-12, B. C.
Johnson, ed., Academic Press, N.Y. (1983); Seifter et al., Meth
Enzymol 182:626-646 (1990); and Rattan et al., Ann NY Acad Sci
663:48-62 (1992).
[0420] The present invention further provides fragments of the
variant proteins in which the fragments contain one or more amino
acid sequence variations (e.g., substitutions, or truncations or
extensions due to creation or destruction of a stop codon) encoded
by one or more SNPs disclosed herein. The fragments to which the
invention pertains, however, are not to be construed as
encompassing fragments that have been disclosed in the prior art
before the present invention.
[0421] As used herein, a fragment may comprise at least about 4, 8,
10, 12, 14, 16, 18, 20, 25, 30, 50, 100 (or any other number
in-between) or more contiguous amino acid residues from a variant
protein, wherein at least one amino acid residue is affected by a
SNP of the present invention, e.g., a variant amino acid residue
encoded by a nonsynonymous nucleotide substitution at a cSNP
position provided by the present invention. The variant amino acid
encoded by a cSNP may occupy any residue position along the
sequence of the fragment. Such fragments can be chosen based on the
ability to retain one or more of the biological activities of the
variant protein or the ability to perform a function, e.g., act as
an immunogen. Particularly important fragments are biologically
active fragments. Such fragments will typically comprise a domain
or motif of a variant protein of the present invention, e.g.,
active site, transmembrane domain, or ligand/substrate binding
domain. Other fragments include, but are not limited to, domain or
motif-containing fragments, soluble peptide fragments, and
fragments containing immunogenic structures. Predicted domains and
functional sites are readily identifiable by computer programs well
known to those of skill in the art (e.g., PROSITE analysis).
Current Protocols in Protein Science, John Wiley & Sons, N.Y.
(2002).
[0422] Uses of Variant Proteins
[0423] The variant proteins of the present invention can be used in
a variety of ways, including but not limited to, in assays to
determine the biological activity of a variant protein, such as in
a panel of multiple proteins for high-throughput screening; to
raise antibodies or to elicit another type of immune response; as a
reagent (including the labeled reagent) in assays designed to
quantitatively determine levels of the variant protein (or its
binding partner) in biological fluids; as a marker for cells or
tissues in which it is preferentially expressed (either
constitutively or at a particular stage of tissue differentiation
or development or in a disease state); as a target for screening
for a therapeutic agent; and as a direct therapeutic agent to be
administered into a human subject. Any of the variant proteins
disclosed herein may be developed into reagent grade or kit format
for commercialization as research products. Methods for performing
the uses listed above are well known to those skilled in the art.
See, e.g., Molecular Cloning: A Laboratory Manual, Sambrook and
Russell, Cold Spring Harbor Laboratory Press, N.Y. (2000), and
Methods in Enzymology: Guide to Molecular Cloning Techniques, S. L.
Berger and A. R. Kimmel, eds., Academic Press (1987).
[0424] In a specific embodiment of the invention, the methods of
the present invention include detection of one or more variant
proteins disclosed herein. Variant proteins are disclosed in Table
1 and in the Sequence Listing as SEQ ID NOS:3-4. Detection of such
proteins can be accomplished using, for example, antibodies, small
molecule compounds, aptamers, ligands/substrates, other proteins or
protein fragments, or other protein-binding agents. Preferably,
protein detection agents are specific for a variant protein of the
present invention and can therefore discriminate between a variant
protein of the present invention and the wild-type protein or
another variant form. This can generally be accomplished by, for
example, selecting or designing detection agents that bind to the
region of a protein that differs between the variant and wild-type
protein, such as a region of a protein that contains one or more
amino acid substitutions that is/are encoded by a non-synonymous
cSNP of the present invention, or a region of a protein that
follows a nonsense mutation-type SNP that creates a stop codon
thereby leading to a shorter polypeptide, or a region of a protein
that follows a read-through mutation-type SNP that destroys a stop
codon thereby leading to a longer polypeptide in which a portion of
the polypeptide is present in one version of the polypeptide but
not the other.
[0425] In another specific aspect of the invention, the variant
proteins of the present invention are used as targets for
diagnosing psoriasis or for determining predisposition to psoriasis
in a human, for treating and/or preventing psoriasis, or for
predicting an individual's response to a drug treatment
(particularly treatment or prevention of psoriasis), etc.
Accordingly, the invention provides methods for detecting the
presence of, or levels of, one or more variant proteins of the
present invention in a cell, tissue, or organism. Such methods
typically involve contacting a test sample with an agent (e.g., an
antibody, small molecule compound, or peptide) capable of
interacting with the variant protein such that specific binding of
the agent to the variant protein can be detected. Such an assay can
be provided in a single detection format or a multi-detection
format such as an array, for example, an antibody or aptamer array
(arrays for protein detection may also be referred to as "protein
chips"). The variant protein of interest can be isolated from a
test sample and assayed for the presence of a variant amino acid
sequence encoded by one or more SNPs disclosed by the present
invention. The SNPs may cause changes to the protein and the
corresponding protein function/activity, such as through
non-synonymous substitutions in protein coding regions that can
lead to amino acid substitutions, deletions, insertions, and/or
rearrangements; formation or destruction of stop codons; or
alteration of control elements such as promoters. SNPs may also
cause inappropriate post-translational modifications.
[0426] One preferred agent for detecting a variant protein in a
sample is an antibody capable of selectively binding to a variant
form of the protein (antibodies are described in greater detail in
the next section). Such samples include, for example, tissues,
cells, and biological fluids isolated from a subject, as well as
tissues, cells and fluids present within a subject.
[0427] In vitro methods for detection of the variant proteins
associated with psoriasis that are disclosed herein and fragments
thereof include, but are not limited to, enzyme linked
immunosorbent assays (ELISAs), radioimmunoassays (RIA), Western
blots, immunoprecipitations, immunofluorescence, and protein
arrays/chips (e.g., arrays of antibodies or aptamers). For further
information regarding immunoassays and related protein detection
methods, see Current Protocols in Immunology, John Wiley &
Sons, N.Y., and Hage, "Immunoassays," Anal Chem 15;
71(12):294R-304R (June 1999).
[0428] Additional analytic methods of detecting amino acid variants
include, but are not limited to, altered electrophoretic mobility,
altered tryptic peptide digest, altered protein activity in
cell-based or cell-free assay, alteration in ligand or
antibody-binding pattern, altered isoelectric point, and direct
amino acid sequencing.
[0429] Alternatively, variant proteins can be detected in vivo in a
subject by introducing into the subject a labeled antibody (or
other type of detection reagent) specific for a variant protein.
For example, the antibody can be labeled with a radioactive marker
whose presence and location in a subject can be detected by
standard imaging techniques.
[0430] Other uses of the variant peptides of the present invention
are based on the class or action of the protein. For example,
proteins isolated from humans and their mammalian orthologs serve
as targets for identifying agents (e.g., small molecule drugs or
antibodies) for use in therapeutic applications, particularly for
modulating a biological or pathological response in a cell or
tissue that expresses the protein. Pharmaceutical agents can be
developed that modulate protein activity.
[0431] As an alternative to modulating gene expression, therapeutic
compounds can be developed that modulate protein function. For
example, many SNPs disclosed herein affect the amino acid sequence
of the encoded protein (e.g., non-synonymous cSNPs and nonsense
mutation-type SNPs). Such alterations in the encoded amino acid
sequence may affect protein function, particularly if such amino
acid sequence variations occur in functional protein domains, such
as catalytic domains, ATP-binding domains, or ligand/substrate
binding domains. It is well established in the art that variant
proteins having amino acid sequence variations in functional
domains can cause or influence pathological conditions. In such
instances, compounds (e.g., small molecule drugs or antibodies) can
be developed that target the variant protein and modulate (e.g.,
up- or down-regulate) protein function/activity.
[0432] The therapeutic methods of the present invention further
include methods that target one or more variant proteins of the
present invention. Variant proteins can be targeted using, for
example, small molecule compounds, antibodies, aptamers,
ligands/substrates, other proteins, or other protein-binding
agents. Additionally, the skilled artisan will recognize that the
novel protein variants (and polymorphic nucleic acid molecules)
disclosed in Table 1 may themselves be directly used as therapeutic
agents by acting as competitive inhibitors of corresponding
art-known proteins (or nucleic acid molecules such as mRNA
molecules).
[0433] The variant proteins of the present invention are
particularly useful in drug screening assays, in cell-based or
cell-free systems. Cell-based systems can utilize cells that
naturally express the protein, a biopsy specimen, or cell cultures.
In one embodiment, cell-based assays involve recombinant host cells
expressing the variant protein. Cell-free assays can be used to
detect the ability of a compound to directly bind to a variant
protein or to the corresponding SNP-containing nucleic acid
fragment that encodes the variant protein.
[0434] A variant protein of the present invention, as well as
appropriate fragments thereof, can be used in high-throughput
screening assays to test candidate compounds for the ability to
bind and/or modulate the activity of the variant protein. These
candidate compounds can be further screened against a protein
having normal function (e.g., a wild-type/non-variant protein) to
further determine the effect of the compound on the protein
activity. Furthermore, these compounds can be tested in animal or
invertebrate systems to determine in vivo activity/effectiveness.
Compounds can be identified that activate (agonists) or inactivate
(antagonists) the variant protein, and different compounds can be
identified that cause various degrees of activation or inactivation
of the variant protein.
[0435] Further, the variant proteins can be used to screen a
compound for the ability to stimulate or inhibit interaction
between the variant protein and a target molecule that normally
interacts with the protein. The target can be a ligand, a substrate
or a binding partner that the protein normally interacts with (for
example, epinephrine or norepinephrine). Such assays typically
include the steps of combining the variant protein with a candidate
compound under conditions that allow the variant protein, or
fragment thereof, to interact with the target molecule, and to
detect the formation of a complex between the protein and the
target or to detect the biochemical consequence of the interaction
with the variant protein and the target, such as any of the
associated effects of signal transduction.
[0436] Candidate compounds include, for example, 1) peptides such
as soluble peptides, including Ig-tailed fusion peptides and
members of random peptide libraries (see, e.g., Lam et al., Nature
354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and
combinatorial chemistry-derived molecular libraries made of D-
and/or L-configuration amino acids; 2) phosphopeptides (e.g.,
members of random and partially degenerate, directed phosphopeptide
libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3)
antibodies (e.g., polyclonal, monoclonal, humanized,
anti-idiotypic, chimeric, and single chain antibodies as well as
Fab, F(ab').sub.2, Fab expression library fragments, and
epitope-binding fragments of antibodies); and 4) small organic and
inorganic molecules (e.g., molecules obtained from combinatorial
and natural product libraries).
[0437] One candidate compound is a soluble fragment of the variant
protein that competes for ligand binding. Other candidate compounds
include mutant proteins or appropriate fragments containing
mutations that affect variant protein function and thus compete for
ligand. Accordingly, a fragment that competes for ligand, for
example with a higher affinity, or a fragment that binds ligand but
does not allow release, is encompassed by the invention.
[0438] The invention further includes other end point assays to
identify compounds that modulate (stimulate or inhibit) variant
protein activity. The assays typically involve an assay of events
in the signal transduction pathway that indicate protein activity.
Thus, the expression of genes that are up or down-regulated in
response to the variant protein dependent signal cascade can be
assayed. In one embodiment, the regulatory region of such genes can
be operably linked to a marker that is easily detectable, such as
luciferase. Alternatively, phosphorylation of the variant protein,
or a variant protein target, could also be measured. Any of the
biological or biochemical functions mediated by the variant protein
can be used as an endpoint assay. These include all of the
biochemical or biological events described herein, in the
references cited herein, incorporated by reference for these
endpoint assay targets, and other functions known to those of
ordinary skill in the art.
[0439] Binding and/or activating compounds can also be screened by
using chimeric variant proteins in which an amino terminal
extracellular domain or parts thereof, an entire transmembrane
domain or subregions, and/or the carboxyl terminal intracellular
domain or parts thereof, can be replaced by heterologous domains or
subregions. For example, a substrate-binding region can be used
that interacts with a different substrate than that which is
normally recognized by a variant protein. Accordingly, a different
set of signal transduction components is available as an end-point
assay for activation. This allows for assays to be performed in
other than the specific host cell from which the variant protein is
derived.
[0440] The variant proteins are also useful in competition binding
assays in methods designed to discover compounds that interact with
the variant protein. Thus, a compound can be exposed to a variant
protein under conditions that allow the compound to bind or to
otherwise interact with the variant protein. A binding partner,
such as ligand, that normally interacts with the variant protein is
also added to the mixture. If the test compound interacts with the
variant protein or its binding partner, it decreases the amount of
complex formed or activity from the variant protein. This type of
assay is particularly useful in screening for compounds that
interact with specific regions of the variant protein. Hodgson,
Bio/technology, 10(9), 973-80 (September 1992).
[0441] To perform cell-free drug screening assays, it is sometimes
desirable to immobilize either the variant protein or a fragment
thereof, or its target molecule, to facilitate separation of
complexes from uncomplexed forms of one or both of the proteins, as
well as to accommodate automation of the assay. Any method for
immobilizing proteins on matrices can be used in drug screening
assays. In one embodiment, a fusion protein containing an added
domain allows the protein to be bound to a matrix. For example,
glutathione-S-transferase/.sup.125I fusion proteins can be adsorbed
onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.)
or glutathione derivatized microtitre plates, which are then
combined with the cell lysates (e.g., .sup.35S-labeled) and a
candidate compound, such as a drug candidate, and the mixture
incubated under conditions conducive to complex formation (e.g., at
physiological conditions for salt and pH). Following incubation,
the beads can be washed to remove any unbound label, and the matrix
immobilized and radiolabel determined directly, or in the
supernatant after the complexes are dissociated. Alternatively, the
complexes can be dissociated from the matrix, separated by
SDS-PAGE, and the level of bound material found in the bead
fraction quantitated from the gel using standard electrophoretic
techniques.
[0442] Either the variant protein or its target molecule can be
immobilized utilizing conjugation of biotin and streptavidin.
Alternatively, antibodies reactive with the variant protein but
which do not interfere with binding of the variant protein to its
target molecule can be derivatized to the wells of the plate, and
the variant protein trapped in the wells by antibody conjugation.
Preparations of the target molecule and a candidate compound are
incubated in the variant protein-presenting wells and the amount of
complex trapped in the well can be quantitated. Methods for
detecting such complexes, in addition to those described above for
the GST-immobilized complexes, include immunodetection of complexes
using antibodies reactive with the protein target molecule, or
which are reactive with variant protein and compete with the target
molecule, and enzyme-linked assays that rely on detecting an
enzymatic activity associated with the target molecule.
[0443] Modulators of variant protein activity identified according
to these drug screening assays can be used to treat a subject with
a disorder mediated by the protein pathway, such as psoriasis.
These methods of treatment typically include the steps of
administering the modulators of protein activity in a
pharmaceutical composition to a subject in need of such
treatment.
[0444] The variant proteins, or fragments thereof, disclosed herein
can themselves be directly used to treat a disorder characterized
by an absence of, inappropriate, or unwanted expression or activity
of the variant protein. Accordingly, methods for treatment include
the use of a variant protein disclosed herein or fragments
thereof.
[0445] In yet another aspect of the invention, variant proteins can
be used as "bait proteins" in a two-hybrid assay or three-hybrid
assay to identify other proteins that bind to or interact with the
variant protein and are involved in variant protein activity. See,
e.g., U.S. Pat. No. 5,283,317; Zervos et al., Cell 72:223-232
(1993); Madura et al., J Biol Chem 268:12046-12054 (1993); Bartel
et al., Biotechniques 14:920-924 (1993); Iwabuchi et al., Oncogene
8:1693-1696 (1993); and Brent, WO 94/10300. Such variant
protein-binding proteins are also likely to be involved in the
propagation of signals by the variant proteins or variant protein
targets as, for example, elements of a protein-mediated signaling
pathway. Alternatively, such variant protein-binding proteins are
inhibitors of the variant protein.
[0446] The two-hybrid system is based on the modular nature of most
transcription factors, which typically consist of separable
DNA-binding and activation domains. Briefly, the assay typically
utilizes two different DNA constructs. In one construct, the gene
that codes for a variant protein is fused to a gene encoding the
DNA binding domain of a known transcription factor (e.g., GAL-4).
In the other construct, a DNA sequence, from a library of DNA
sequences, that encodes an unidentified protein ("prey" or
"sample") is fused to a gene that codes for the activation domain
of the known transcription factor. If the "bait" and the "prey"
proteins are able to interact, in vivo, forming a variant
protein-dependent complex, the DNA-binding and activation domains
of the transcription factor are brought into close proximity. This
proximity allows transcription of a reporter gene (e.g., LacZ) that
is operably linked to a transcriptional regulatory site responsive
to the transcription factor. Expression of the reporter gene can be
detected, and cell colonies containing the functional transcription
factor can be isolated and used to obtain the cloned gene that
encodes the protein that interacts with the variant protein.
[0447] Antibodies Directed to Variant Proteins
[0448] The present invention also provides antibodies that
selectively bind to the variant proteins disclosed herein and
fragments thereof. Such antibodies may be used to quantitatively or
qualitatively detect the variant proteins of the present invention.
As used herein, an antibody selectively binds a target variant
protein when it binds the variant protein and does not
significantly bind to non-variant proteins, i.e., the antibody does
not significantly bind to normal, wild-type, or art-known proteins
that do not contain a variant amino acid sequence due to one or
more SNPs of the present invention (variant amino acid sequences
may be due to, for example, nonsynonymous cSNPs, nonsense SNPs that
create a stop codon, thereby causing a truncation of a polypeptide
or SNPs that cause read-through mutations resulting in an extension
of a polypeptide).
[0449] As used herein, an antibody is defined in terms consistent
with that recognized in the art: they are multi-subunit proteins
produced by an organism in response to an antigen challenge. The
antibodies of the present invention include both monoclonal
antibodies and polyclonal antibodies, as well as antigen-reactive
proteolytic fragments of such antibodies, such as Fab,
F(ab)'.sub.2, and Fv fragments. In addition, an antibody of the
present invention further includes any of a variety of engineered
antigen-binding molecules such as a chimeric antibody (U.S. Pat.
Nos. 4,816,567 and 4,816,397; Morrison et al., Proc Natl Acad Sci
USA 81:6851 (1984); Neuberger et al., Nature 312:604 (1984)), a
humanized antibody (U.S. Pat. Nos. 5,693,762; 5,585,089 and
5,565,332), a single-chain Fv (U.S. Pat. No. 4,946,778; Ward et
al., Nature 334:544 (1989)), a bispecific antibody with two binding
specificities (Segal et al., J Immunol Methods 248:1 (2001);
Carter, J Immunol Methods 248:7 (2001)), a diabody, a triabody, and
a tetrabody (Todorovska et al., J Immunol Methods 248:47 (2001)),
as well as a Fab conjugate (dimer or trimer), and a minibody.
[0450] Many methods are known in the art for generating and/or
identifying antibodies to a given target antigen. Harlow,
Antibodies, Cold Spring Harbor Press, N.Y. (1989). In general, an
isolated peptide (e.g., a variant protein of the present invention)
is used as an immunogen and is administered to a mammalian
organism, such as a rat, rabbit, hamster or mouse. Either a
full-length protein, an antigenic peptide fragment (e.g., a peptide
fragment containing a region that varies between a variant protein
and a corresponding wild-type protein), or a fusion protein can be
used. A protein used as an immunogen may be naturally-occurring,
synthetic or recombinantly produced, and may be administered in
combination with an adjuvant, including but not limited to,
Freund's (complete and incomplete), mineral gels such as aluminum
hydroxide, surface active substance such as lysolecithin, pluronic
polyols, polyanions, peptides, oil emulsions, keyhole limpet
hemocyanin, dinitrophenol, and the like.
[0451] Monoclonal antibodies can be produced by hybridoma
technology, which immortalizes cells secreting a specific
monoclonal antibody. Kohler and Milstein, Nature 256:495 (1975).
The immortalized cell lines can be created in vitro by fusing two
different cell types, typically lymphocytes, and tumor cells. The
hybridoma cells may be cultivated in vitro or in vivo.
Additionally, fully human antibodies can be generated by transgenic
animals. He et al., J Immunol 169:595 (2002). Fd phage and Fd
phagemid technologies may be used to generate and select
recombinant antibodies in vitro. Hoogenboom and Chames, Immunol
Today 21:371 (2000); Liu et al., J Mol Biol 315:1063 (2002). The
complementarity-determining regions of an antibody can be
identified, and synthetic peptides corresponding to such regions
may be used to mediate antigen binding. U.S. Pat. No.
5,637,677.
[0452] Antibodies are preferably prepared against regions or
discrete fragments of a variant protein containing a variant amino
acid sequence as compared to the corresponding wild-type protein
(e.g., a region of a variant protein that includes an amino acid
encoded by a nonsynonymous cSNP, a region affected by truncation
caused by a nonsense SNP that creates a stop codon, or a region
resulting from the destruction of a stop codon due to read-through
mutation caused by a SNP). Furthermore, preferred regions will
include those involved in function/activity and/or protein/binding
partner interaction. Such fragments can be selected on a physical
property, such as fragments corresponding to regions that are
located on the surface of the protein, e.g., hydrophilic regions,
or can be selected based on sequence uniqueness, or based on the
position of the variant amino acid residue(s) encoded by the SNPs
provided by the present invention. An antigenic fragment will
typically comprise at least about 8-10 contiguous amino acid
residues in which at least one of the amino acid residues is an
amino acid affected by a SNP disclosed herein. The antigenic
peptide can comprise, however, at least 12, 14, 16, 20, 25, 50, 100
(or any other number in-between) or more amino acid residues,
provided that at least one amino acid is affected by a SNP
disclosed herein.
[0453] Detection of an antibody of the present invention can be
facilitated by coupling (i.e., physically linking) the antibody or
an antigen-reactive fragment thereof to a detectable substance.
Detectable substances include, but are not limited to, various
enzymes, prosthetic groups, fluorescent materials, luminescent
materials, bioluminescent materials, and radioactive materials.
Examples of suitable enzymes include horseradish peroxidase,
alkaline phosphatase, .beta.-galactosidase, or
acetylcholinesterase; examples of suitable prosthetic group
complexes include streptavidin/biotin and avidin/biotin; examples
of suitable fluorescent materials include umbelliferone,
fluorescein, fluorescein isothiocyanate, rhodamine,
dichlorotriazinylamine fluorescein, dansyl chloride or
phycoerythrin; an example of a luminescent material includes
luminol; examples of bioluminescent materials include luciferase,
luciferin, and aequorin, and examples of suitable radioactive
material include .sup.125I, .sup.131I, .sup.35S or .sup.3H.
[0454] Antibodies, particularly the use of antibodies as
therapeutic agents, are reviewed in: Morgan, "Antibody therapy for
Alzheimer's disease," Expert Rev Vaccines (1):53-9 (February 2003);
Ross et al., "Anticancer antibodies," Am J Clin Pathol
119(4):472-85 (April 2003); Goldenberg, "Advancing role of
radiolabeled antibodies in the therapy of cancer," Cancer Immunol
Immunother 52(5):281-96 (May 2003); Epub Mar. 11, 2003; Ross et
al., "Antibody-based therapeutics in oncology," Expert Rev
Anticancer Ther 3(1):107-21 (February 2003); Cao et al.,
"Bispecific antibody conjugates in therapeutics," Adv Drug Deliv
Rev 55(2):171-97 (February 2003); von Mehren et al., "Monoclonal
antibody therapy for cancer," Annu Rev Med 54:343-69 (2003); Epub
Dec. 3, 2001; Hudson et al., "Engineered antibodies," Nat Med
9(1):129-34 (January 2003); Brekke et al., "Therapeutic antibodies
for human diseases at the dawn of the twenty-first century," Nat
Rev Drug Discov 2(1):52-62 (January 2003); Erratum in: Nat Rev Drug
Discov 2(3):240 (March 2003); Houdebine, "Antibody manufacture in
transgenic animals and comparisons with other systems," Curr Opin
Biotechnol 13(6):625-9 (December 2002); Andreakos et al.,
"Monoclonal antibodies in immune and inflammatory diseases," Curr
Opin Biotechnol 13(6):615-20 (December 2002); Kellermann et al.,
"Antibody discovery: the use of transgenic mice to generate human
monoclonal antibodies for therapeutics," Curr Opin Biotechnol
13(6):593-7 (December 2002); Pini et al., "Phage display and colony
filter screening for high-throughput selection of antibody
libraries," Comb Chem High Throughput Screen 5(7):503-10 (November
2002); Batra et al., "Pharmacokinetics and biodistribution of
genetically engineered antibodies," Curr Opin Biotechnol
13(6):603-8 (December 2002); and Tangri et al., "Rationally
engineered proteins or antibodies with absent or reduced
immunogenicity," Curr Med Chem 9(24):2191-9 (December 2002).
[0455] Uses of Antibodies
[0456] Antibodies can be used to isolate the variant proteins of
the present invention from a natural cell source or from
recombinant host cells by standard techniques, such as affinity
chromatography or immunoprecipitation. In addition, antibodies are
useful for detecting the presence of a variant protein of the
present invention in cells or tissues to determine the pattern of
expression of the variant protein among various tissues in an
organism and over the course of normal development or disease
progression. Further, antibodies can be used to detect variant
protein in situ, in vitro, in a bodily fluid, or in a cell lysate
or supernatant in order to evaluate the amount and pattern of
expression. Also, antibodies can be used to assess abnormal tissue
distribution, abnormal expression during development, or expression
in an abnormal condition, such as in psoriasis, or during drug
treatment. Additionally, antibody detection of circulating
fragments of the full-length variant protein can be used to
identify turnover.
[0457] Antibodies to the variant proteins of the present invention
are also useful in pharmacogenomic analysis. Thus, antibodies
against variant proteins encoded by alternative SNP alleles can be
used to identify individuals that require modified treatment
modalities.
[0458] Further, antibodies can be used to assess expression of the
variant protein in disease states such as in active stages of the
disease or in an individual with a predisposition to a disease
related to the protein's function, such as psoriasis, or during the
course of a treatment regime. Antibodies specific for a variant
protein encoded by a SNP-containing nucleic acid molecule of the
present invention can be used to assay for the presence of the
variant protein, such as to diagnose psoriasis or to predict an
individual's response to a drug treatment or
predisposition/susceptibility to psoriasis, as indicated by the
presence of the variant protein.
[0459] Antibodies are also useful as diagnostic tools for
evaluating the variant proteins in conjunction with analysis by
electrophoretic mobility, isoelectric point, tryptic peptide
digest, and other physical assays well known in the art.
[0460] Antibodies are also useful for tissue typing. Thus, where a
specific variant protein has been correlated with expression in a
specific tissue, antibodies that are specific for this protein can
be used to identify a tissue type.
[0461] Antibodies can also be used to assess aberrant subcellular
localization of a variant protein in cells in various tissues. The
diagnostic uses can be applied, not only in genetic testing, but
also in monitoring a treatment modality. Accordingly, where
treatment is ultimately aimed at correcting the expression level or
the presence of variant protein or aberrant tissue distribution or
developmental expression of a variant protein, antibodies directed
against the variant protein or relevant fragments can be used to
monitor therapeutic efficacy.
[0462] The antibodies are also useful for inhibiting variant
protein function, for example, by blocking the binding of a variant
protein to a binding partner. These uses can also be applied in a
therapeutic context in which treatment involves inhibiting a
variant protein's function. An antibody can be used, for example,
to block or competitively inhibit binding, thus modulating
(agonizing or antagonizing) the activity of a variant protein.
Antibodies can be prepared against specific variant protein
fragments containing sites required for function or against an
intact variant protein that is associated with a cell or cell
membrane. For in vivo administration, an antibody may be linked
with an additional therapeutic payload such as a radionuclide, an
enzyme, an immunogenic epitope, or a cytotoxic agent. Suitable
cytotoxic agents include, but are not limited to, bacterial toxin
such as diphtheria, and plant toxin such as ricin. The in vivo
half-life of an antibody or a fragment thereof may be lengthened by
pegylation through conjugation to polyethylene glycol. Leong et
al., Cytokine 16:106 (2001).
[0463] The invention also encompasses kits for using antibodies,
such as kits for detecting the presence of a variant protein in a
test sample. An exemplary kit can comprise antibodies such as a
labeled or labelable antibody and a compound or agent for detecting
variant proteins in a biological sample; means for determining the
amount, or presence/absence of variant protein in the sample; means
for comparing the amount of variant protein in the sample with a
standard; and instructions for use.
[0464] Vectors and Host Cells
[0465] The present invention also provides vectors containing the
SNP-containing nucleic acid molecules described herein. The term
"vector" refers to a vehicle, preferably a nucleic acid molecule,
which can transport a SNP-containing nucleic acid molecule. When
the vector is a nucleic acid molecule, the SNP-containing nucleic
acid molecule can be covalently linked to the vector nucleic acid.
Such vectors include, but are not limited to, a plasmid, single or
double stranded phage, a single or double stranded RNA or DNA viral
vector, or artificial chromosome, such as a BAC, PAC, YAC, or
MAC.
[0466] A vector can be maintained in a host cell as an
extrachromosomal element where it replicates and produces
additional copies of the SNP-containing nucleic acid molecules.
Alternatively, the vector may integrate into the host cell genome
and produce additional copies of the SNP-containing nucleic acid
molecules when the host cell replicates.
[0467] The invention provides vectors for the maintenance (cloning
vectors) or vectors for expression (expression vectors) of the
SNP-containing nucleic acid molecules. The vectors can function in
prokaryotic or eukaryotic cells or in both (shuttle vectors).
[0468] Expression vectors typically contain cis-acting regulatory
regions that are operably linked in the vector to the
SNP-containing nucleic acid molecules such that transcription of
the SNP-containing nucleic acid molecules is allowed in a host
cell. The SNP-containing nucleic acid molecules can also be
introduced into the host cell with a separate nucleic acid molecule
capable of affecting transcription. Thus, the second nucleic acid
molecule may provide a trans-acting factor interacting with the
cis-regulatory control region to allow transcription of the
SNP-containing nucleic acid molecules from the vector.
Alternatively, a trans-acting factor may be supplied by the host
cell. Finally, a trans-acting factor can be produced from the
vector itself. It is understood, however, that in some embodiments,
transcription and/or translation of the nucleic acid molecules can
occur in a cell-free system.
[0469] The regulatory sequences to which the SNP-containing nucleic
acid molecules described herein can be operably linked include
promoters for directing mRNA transcription. These include, but are
not limited to, the left promoter from bacteriophage .lamda., the
lac, TRP, and TAC promoters from E. coli, the early and late
promoters from SV40, the CMV immediate early promoter, the
adenovirus early and late promoters, and retrovirus long-terminal
repeats.
[0470] In addition to control regions that promote transcription,
expression vectors may also include regions that modulate
transcription, such as repressor binding sites and enhancers.
Examples include the SV40 enhancer, the cytomegalovirus immediate
early enhancer, polyoma enhancer, adenovirus enhancers, and
retrovirus LTR enhancers.
[0471] In addition to containing sites for transcription initiation
and control, expression vectors can also contain sequences
necessary for transcription termination and, in the transcribed
region, a ribosome-binding site for translation. Other regulatory
control elements for expression include initiation and termination
codons as well as polyadenylation signals. A person of ordinary
skill in the art would be aware of the numerous regulatory
sequences that are useful in expression vectors. See, e.g.,
Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold
Spring Harbor Laboratory Press, N.Y. (2000).
[0472] A variety of expression vectors can be used to express a
SNP-containing nucleic acid molecule. Such vectors include
chromosomal, episomal, and virus-derived vectors, for example,
vectors derived from bacterial plasmids, from bacteriophage, from
yeast episomes, from yeast chromosomal elements, including yeast
artificial chromosomes, from viruses such as baculoviruses,
papovaviruses such as SV40, Vaccinia viruses, adenoviruses,
poxviruses, pseudorabies viruses, and retroviruses. Vectors can
also be derived from combinations of these sources such as those
derived from plasmid and bacteriophage genetic elements, e.g.,
cosmids and phagemids. Appropriate cloning and expression vectors
for prokaryotic and eukaryotic hosts are described in Sambrook and
Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor
Laboratory Press, N.Y. (2000).
[0473] The regulatory sequence in a vector may provide constitutive
expression in one or more host cells (e.g., tissue specific
expression) or may provide for inducible expression in one or more
cell types such as by temperature, nutrient additive, or exogenous
factor, e.g., a hormone or other ligand. A variety of vectors that
provide constitutive or inducible expression of a nucleic acid
sequence in prokaryotic and eukaryotic host cells are well known to
those of ordinary skill in the art.
[0474] A SNP-containing nucleic acid molecule can be inserted into
the vector by methodology well-known in the art. Generally, the
SNP-containing nucleic acid molecule that will ultimately be
expressed is joined to an expression vector by cleaving the
SNP-containing nucleic acid molecule and the expression vector with
one or more restriction enzymes and then ligating the fragments
together. Procedures for restriction enzyme digestion and ligation
are well known to those of ordinary skill in the art.
[0475] The vector containing the appropriate nucleic acid molecule
can be introduced into an appropriate host cell for propagation or
expression using well-known techniques. Bacterial host cells
include, but are not limited to, Escherichia coli, Streptomyces
spp., and Salmonella typhimurium. Eukaryotic host cells include,
but are not limited to, yeast, insect cells such as Drosophila
spp., animal cells such as COS and CHO cells, and plant cells.
[0476] As described herein, it may be desirable to express the
variant peptide as a fusion protein. Accordingly, the invention
provides fusion vectors that allow for the production of the
variant peptides. Fusion vectors can, for example, increase the
expression of a recombinant protein, increase the solubility of the
recombinant protein, and aid in the purification of the protein by
acting, for example, as a ligand for affinity purification. A
proteolytic cleavage site may be introduced at the junction of the
fusion moiety so that the desired variant peptide can ultimately be
separated from the fusion moiety. Proteolytic enzymes suitable for
such use include, but are not limited to, factor Xa, thrombin, and
enterokinase. Typical fusion expression vectors include pGEX (Smith
et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly,
Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse
glutathione S-transferase (GST), maltose E binding protein, or
protein A, respectively, to the target recombinant protein.
Examples of suitable inducible non-fusion E. coli expression
vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET
11d (Studier et al., Gene Expression Technology: Methods in
Enzymology 185:60-89 (1990)).
[0477] Recombinant protein expression can be maximized in a
bacterial host by providing a genetic background wherein the host
cell has an impaired capacity to proteolytically cleave the
recombinant protein (S. Gottesman, Gene Expression Technology:
Methods in Enzymology 185:119-128, Academic Press, Calif. (1990)).
Alternatively, the sequence of the SNP-containing nucleic acid
molecule of interest can be altered to provide preferential codon
usage for a specific host cell, for example, E. coli. Wada et al.,
Nucleic Acids Res 20:2111-2118 (1992).
[0478] The SNP-containing nucleic acid molecules can also be
expressed by expression vectors that are operative in yeast.
Examples of vectors for expression in yeast (e.g., S. cerevisiae)
include pYepSec1 (Baldari et al., EMBO J 6:229-234 (1987)), pMFa
(Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al.,
Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San
Diego, Calif.).
[0479] The SNP-containing nucleic acid molecules can also be
expressed in insect cells using, for example, baculovirus
expression vectors. Baculovirus vectors available for expression of
proteins in cultured insect cells (e.g., Sf 9 cells) include the
pAc series (Smith et al., Mol Cell Biol 3:2156-2165 (1983)) and the
pVL series (Lucklow et al., Virology 170:31-39 (1989)).
[0480] In certain embodiments of the invention, the SNP-containing
nucleic acid molecules described herein are expressed in mammalian
cells using mammalian expression vectors. Examples of mammalian
expression vectors include pCDM8 (B. Seed, Nature 329:840(1987))
and pMT2PC (Kaufman et al., EMBO J 6:187-195 (1987)).
[0481] The invention also encompasses vectors in which the
SNP-containing nucleic acid molecules described herein are cloned
into the vector in reverse orientation, but operably linked to a
regulatory sequence that permits transcription of antisense RNA.
Thus, an antisense transcript can be produced to the SNP-containing
nucleic acid sequences described herein, including both coding and
non-coding regions. Expression of this antisense RNA is subject to
each of the parameters described above in relation to expression of
the sense RNA (regulatory sequences, constitutive or inducible
expression, tissue-specific expression).
[0482] The invention also relates to recombinant host cells
containing the vectors described herein. Host cells therefore
include, for example, prokaryotic cells, lower eukaryotic cells
such as yeast, other eukaryotic cells such as insect cells, and
higher eukaryotic cells such as mammalian cells.
[0483] The recombinant host cells can be prepared by introducing
the vector constructs described herein into the cells by techniques
readily available to persons of ordinary skill in the art. These
include, but are not limited to, calcium phosphate transfection,
DEAE-dextran-mediated transfection, cationic lipid-mediated
transfection, electroporation, transduction, infection,
lipofection, and other techniques such as those described in
Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold
Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, N.Y.
(2000).
[0484] Host cells can contain more than one vector. Thus, different
SNP-containing nucleotide sequences can be introduced in different
vectors into the same cell. Similarly, the SNP-containing nucleic
acid molecules can be introduced either alone or with other nucleic
acid molecules that are not related to the SNP-containing nucleic
acid molecules, such as those providing trans-acting factors for
expression vectors. When more than one vector is introduced into a
cell, the vectors can be introduced independently, co-introduced,
or joined to the nucleic acid molecule vector.
[0485] In the case of bacteriophage and viral vectors, these can be
introduced into cells as packaged or encapsulated virus by standard
procedures for infection and transduction. Viral vectors can be
replication-competent or replication-defective. In the case in
which viral replication is defective, replication can occur in host
cells that provide functions that complement the defects.
[0486] Vectors generally include selectable markers that enable the
selection of the subpopulation of cells that contain the
recombinant vector constructs. The marker can be inserted in the
same vector that contains the SNP-containing nucleic acid molecules
described herein or may be in a separate vector. Markers include,
for example, tetracycline or ampicillin-resistance genes for
prokaryotic host cells, and dihydrofolate reductase or neomycin
resistance genes for eukaryotic host cells. However, any marker
that provides selection for a phenotypic trait can be
effective.
[0487] While the mature variant proteins can be produced in
bacteria, yeast, mammalian cells, and other cells under the control
of the appropriate regulatory sequences, cell-free transcription
and translation systems can also be used to produce these variant
proteins using RNA derived from the DNA constructs described
herein.
[0488] Where secretion of the variant protein is desired, which is
difficult to achieve with multi-transmembrane domain containing
proteins such as G-protein-coupled receptors (GPCRs), appropriate
secretion signals can be incorporated into the vector. The signal
sequence can be endogenous to the peptides or heterologous to these
peptides.
[0489] Where the variant protein is not secreted into the medium,
the protein can be isolated from the host cell by standard
disruption procedures, including freeze/thaw, sonication,
mechanical disruption, use of lysing agents, and the like. The
variant protein can then be recovered and purified by well-known
purification methods including, for example, ammonium sulfate
precipitation, acid extraction, anion or cationic exchange
chromatography, phosphocellulose chromatography,
hydrophobic-interaction chromatography, affinity chromatography,
hydroxylapatite chromatography, lectin chromatography, or high
performance liquid chromatography.
[0490] It is also understood that, depending upon the host cell in
which recombinant production of the variant proteins described
herein occurs, they can have various glycosylation patterns, or may
be non-glycosylated, as when produced in bacteria. In addition, the
variant proteins may include an initial modified methionine in some
cases as a result of a host-mediated process.
[0491] For further information regarding vectors and host cells,
see Current Protocols in Molecular Biology, John Wiley & Sons,
N.Y.
[0492] Uses of Vectors and Host Cells, and Transgenic Animals
[0493] Recombinant host cells that express the variant proteins
described herein have a variety of uses. For example, the cells are
useful for producing a variant protein that can be further purified
into a preparation of desired amounts of the variant protein or
fragments thereof. Thus, host cells containing expression vectors
are useful for variant protein production.
[0494] Host cells are also useful for conducting cell-based assays
involving the variant protein or variant protein fragments, such as
those described above as well as other formats known in the art.
Thus, a recombinant host cell expressing a variant protein is
useful for assaying compounds that stimulate or inhibit variant
protein function. Such an ability of a compound to modulate variant
protein function may not be apparent from assays of the compound on
the native/wild-type protein, or from cell-free assays of the
compound. Recombinant host cells are also useful for assaying
functional alterations in the variant proteins as compared with a
known function.
[0495] Genetically-engineered host cells can be further used to
produce non-human transgenic animals. A transgenic animal is
preferably a non-human mammal, for example, a rodent, such as a rat
or mouse, in which one or more of the cells of the animal include a
transgene. A transgene is exogenous DNA containing a SNP of the
present invention which is integrated into the genome of a cell
from which a transgenic animal develops and which remains in the
genome of the mature animal in one or more of its cell types or
tissues. Such animals are useful for studying the function of a
variant protein in vivo, and identifying and evaluating modulators
of variant protein activity. Other examples of transgenic animals
include, but are not limited to, non-human primates, sheep, dogs,
cows, goats, chickens, and amphibians. Transgenic non-human mammals
such as cows and goats can be used to produce variant proteins
which can be secreted in the animal's milk and then recovered.
[0496] A transgenic animal can be produced by introducing a
SNP-containing nucleic acid molecule into the male pronuclei of a
fertilized oocyte, e.g., by microinjection or retroviral infection,
and allowing the oocyte to develop in a pseudopregnant female
foster animal. Any nucleic acid molecules that contain one or more
SNPs of the present invention can potentially be introduced as a
transgene into the genome of a non-human animal.
[0497] Any of the regulatory or other sequences useful in
expression vectors can form part of the transgenic sequence. This
includes intronic sequences and polyadenylation signals, if not
already included. A tissue-specific regulatory sequence(s) can be
operably linked to the transgene to direct expression of the
variant protein in particular cells or tissues.
[0498] Methods for generating transgenic animals via embryo
manipulation and microinjection, particularly animals such as mice,
have become conventional in the art and are described, for example,
in U.S. Pat. Nos. 4,736,866 and 4,870,009, both by Leder et al.;
U.S. Pat. No. 4,873,191 by Wagner et al., and in B. Hogan,
Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press,
N.Y. (1986). Similar methods are used for production of other
transgenic animals. A transgenic founder animal can be identified
based upon the presence of the transgene in its genome and/or
expression of transgenic mRNA in tissues or cells of the animals. A
transgenic founder animal can then be used to breed additional
animals carrying the transgene. Moreover, transgenic animals
carrying a transgene can further be bred to other transgenic
animals carrying other transgenes. A transgenic animal also
includes a non-human animal in which the entire animal or tissues
in the animal have been produced using the homologously recombinant
host cells described herein.
[0499] In another embodiment, transgenic non-human animals can be
produced which contain selected systems that allow for regulated
expression of the transgene. One example of such a system is the
cre/loxP recombinase system of bacteriophage P1. Lakso et al., PNAS
89:6232-6236 (1992). Another example of a recombinase system is the
FLP recombinase system of S. cerevisiae. O'Gorman et al., Science
251:1351-1355 (1991). If a cre/loxP recombinase system is used to
regulate expression of the transgene, animals containing transgenes
encoding both the Cre recombinase and a selected protein are
generally needed. Such animals can be provided through the
construction of "double" transgenic animals, e.g., by mating two
transgenic animals, one containing a transgene encoding a selected
variant protein and the other containing a transgene encoding a
recombinase.
[0500] Clones of the non-human transgenic animals described herein
can also be produced according to the methods described, for
example, in I. Wilmut et al., Nature 385:810-813 (1997) and PCT
International Publication Nos. WO 97/07668 and WO 97/07669. In
brief, a cell (e.g., a somatic cell) from the transgenic animal can
be isolated and induced to exit the growth cycle and enter G.sub.o
phase. The quiescent cell can then be fused, e.g., through the use
of electrical pulses, to an enucleated oocyte from an animal of the
same species from which the quiescent cell is isolated. The
reconstructed oocyte is then cultured such that it develops to
morula or blastocyst and then transferred to pseudopregnant female
foster animal. The offspring born of this female foster animal will
be a clone of the animal from which the cell (e.g., a somatic cell)
is isolated.
[0501] Transgenic animals containing recombinant cells that express
the variant proteins described herein are useful for conducting the
assays described herein in an in vivo context. Accordingly, the
various physiological factors that are present in vivo and that
could influence ligand or substrate binding, variant protein
activation, signal transduction, or other processes or
interactions, may not be evident from in vitro cell-free or
cell-based assays. Thus, non-human transgenic animals of the
present invention may be used to assay in vivo variant protein
function as well as the activities of a therapeutic agent or
compound that modulates variant protein function/activity or
expression. Such animals are also suitable for assessing the
effects of null mutations (i.e., mutations that substantially or
completely eliminate one or more variant protein functions).
[0502] For further information regarding transgenic animals, see
Houdebine, "Antibody manufacture in transgenic animals and
comparisons with other systems," Curr Opin Biotechnol 13(6):625-9
(December 2002); Petters et al., "Transgenic animals as models for
human disease," Transgenic Res 9(4-5):347-51, discussion 345-6
(2000); Wolf et al., "Use of transgenic animals in understanding
molecular mechanisms of toxicity," J Pharm Pharmacol 50(6):567-74
(June 1998); Echelard, "Recombinant protein production in
transgenic animals," Curr Opin Biotechnol 7(5):536-40 (October
1996); Houdebine, "Transgenic animal bioreactors," Transgenic Res
9(4-5):305-20 (2000); Pirity et al., "Embryonic stem cells,
creating transgenic animals," Methods Cell Biol 57:279-93 (1998);
and Robl et al., "Artificial chromosome vectors and expression of
complex proteins in transgenic animals," Theriogenology
59(1):107-13 (January 2003).
EXAMPLES
[0503] The following examples are offered to illustrate, but not
limit, the claimed invention.
Example 1
Identification and Analysis of Haplotypes in the IL23R Region
Associated with Psoriasis
[0504] Overview
[0505] To analyze the association of IL23R with psoriasis, a fine
mapping strategy was used to identify 59 additional IL23R-linked
SNPs which were genotyped in three independent, white North
American sample sets (>2800 individuals in tow). A sliding
window of haplotype association demonstrates co-localization of
psoriasis susceptibility effects within the boundaries of IL23R
across all sample sets, thereby decreasing the likelihood that
neighboring genes, particularly IL12RB2, are driving the
association at this region. Additional haplotype work identified
two 5-SNP haplotypes with strong protective effects, consistent
across the three sample sets (OR.sub.common=0.67;
P.sub.comb=4.32E-07). Importantly, heterogeneity of effect was
extremely low between sample sets for these haplotypes
(P.sub.Het=0.961). Together, these protective haplotypes attain a
frequency of 16% in controls, declining to 11% in cases. The
characterization of association patterns within IL23R to specific
predisposing/protective variants enables uses of IL23R variants for
determining an individual's risk for developing psoriasis (as well
as related pathologies such as Crohn's disease) and for predicting
an individual's response to various pharmaceutical therapies and
dosages, as well as other uses.
[0506] Results
[0507] Genotyping for this study was performed on three independent
sample sets consisting of white North American psoriasis cases and
controls, totaling 1444 cases and 1382 controls. Basic demographic
and clinical characteristics of these sample sets are described in
a previous publication..sup.2 A type of genomic-control analysis
was performed on pooled genotype data from the initial sample set
which effectively ruled out large population stratification
effects..sup.2
[0508] Applying a fine mapping SNP selection algorithm (described
in the "Materials and Methods" section of Example 1 below), 59
additional SNPs were identified for interrogation in the three
sample sets, for a total of 61 SNPs covering 338 kb (rs7530511,
P310L; and rs11209026, R381Q were previously genotyped in all three
sample sets). 31 of these fine mapping SNPs were within the coding
region or the 3'UTR of IL23R.
[0509] Of the 61 SNPs evaluated, eight had Mantel-Haenszel
continuity-corrected P-values (MH P-values combine association
evidence across the three samples sets, accounting for direction of
effect) below 0.05 (data not shown). Allele frequencies, genotypic
2-df P-values and P-values for the exact test of Hardy-Weinberg
equilibrium for each sample set were also determined for these
SNPs, as well as Mantel-Haenszel allelic odds ratio and 95%
confidence intervals (which were calculated jointly across the
three sample sets) (data not shown). Six of these eight significant
SNPs reside within the IL23R coding region and the remaining two
are located in the intergenic region between IL23R and IL12RB2.
These eight SNPs include two previously reported missense SNPs,
rs7530511 (P310L) and rs11209026 (R381Q).
[0510] Prior to tests of haplotype association, two types of
graphical representations of linkage disequilibrium patterns were
constructed: To characterize the pairwise correlation structure for
the entire 338 kb region, a heatmap for cases and controls combined
using the r.sup.2 and D' statistics was generated (not shown).
Individual pairwise LD values with corresponding SNPs were
calculated (data not shown). All three sample sets were combined
for this analysis. The r.sup.2 heatmap showed an absence of solid
block patterns. Rather, there are two very roughly-defined block
structures in the region with slightly higher average r.sup.2
values than the surrounding regions. These weak blocks are highly
peppered with pairwise comparisons of low LD. More pronounced LD
structure is displayed in the D' heatmap, with two or three blocks
covering the region. Given the fine mapping SNP selection procedure
employed where SNPs were genotyped if they exhibited high LD (as
measured by r.sup.2) with one of the originally associated missense
SNPs (P310L or R381Q) and other SNPs were tagging SNPs reducing
redundancy, the observance of strong block structures was
unexpected. From the r.sup.2 data, the first weak block extends
roughly from intron 3 of C1orf141 into the 5' region of IL12RB2 and
the second weak block covers part of the first intron of IL12RB2
through 28 kb 5' of SERBP1.
[0511] Because much of the association signal was driven by
rs11209026 (R381Q) and other studies have identified this missense
polymorphism as being strongly associated with the related
phenotypes studied, the Mantel-Haenzsel P-value (combining the
three sample sets) was plotted as a function of r.sup.2 with R381Q
(not shown). Under a model where R381Q is solely and causally
responsible for the association patterns observed, one would expect
the approximate relationship: log P.sub.M.apprxeq.r.sup.2 log
P.sub.D; where P.sub.M is the association P-value at a marker in
linkage disequilibrium with the causative site, P.sub.D is the
association P-value at the causative site, in this case R381Q,
r.sup.2 is the pairwise LD measure between the two sites and equal
numbers of genotypes are assayed at each site. This association
decay analysis suggests that some SNPs in low LD with R381Q may
independently contribute to disease status as they substantially
depart from the expected relationship.
[0512] In a previous publication, haplotypes for P310L and R381Q
were constructed since haplotype association tests can be more
informative than single marker test under many models where
cis-effects play an important role..sup.34 Even though these SNPs
were not in high LD, the number of double heterozygotes was small
and hence linkage phase is unambiguous in the large majority of
individuals. With these two missense polymorphisms, carrying the
proline-arginine polypeptide-encoding gene shows susceptible
effects whereas both the leucine-arginine and proline-glutamine
polypeptides confer protective effects. For this study, the fine
mapping data was used to scan this region positionally for
haplotype effects using a sliding window approach. A window size of
three adjacent SNPs was used. A positional plot of the global
haplotype P-value for each window was generated (not shown). The
plot showed an analysis combined across sample sets using the
Fisher's combined P-value method. The results indicated rather
narrow peaks of association centering on IL23R intron 8 through
intron 9 and including the R381Q polymorphism in exon 9--a span of
12 kb. Four SNPs generated this association signal: rs10789229,
rs10889671, rs11209026 (R381Q), and rs10889674; with the first
window (rs10789229-rs10889671-rs11209026) producing a combined
global P-value (2-tailed in each sample set) of 1.28E-04 and the
second window (rs10889671-rs11209026-rs10889674) producing a
combined global P-value (also 2-tailed in each sample set) of
6.42E-05. Through the association and LD analyses, it was apparent
that although these four IL23R SNPs generated the peak association
signal, additional psoriasis-association effects may be possible
through haplotypes derived from additional SNPs (e.g., P310L).
Analysis of pairwise LD and association results indicates that
within the eight SNPs having significant Mantel-Haenszel P-values,
rs7530511 is highly correlated with rs10889671 (intron 8, IL23R
SNP; r.sup.2=0.943); and similarly, rs11209026 is highly correlated
with rs11465804 (intron 8, IL23R SNP; r.sup.2=0.852). These data
were then interrogated with several subsequent haplotype
analyses.
[0513] Another haplotype-based investigation was commenced by using
the five SNPs that exhibited the strongest and most consistent
single-SNP association signals: rs7530511, rs11465804, rs10889671,
rs11209026 and rs1857292. These SNPs span 53 kb from exon 7 in
IL23R to the intergenic region between IL23R and IL12RB2. The
five-SNP haplotypes were estimated and tested for association in
the three sample sets. Five primary haplotypes were found (above 1%
frequency), two of which conferred significant protection against
psoriasis susceptibility (Table 5). Together, these two (completely
divergent) protective haplotypes, TTAGT and CGGAA, were present on
16% of control chromosomes, decreasing to 11% in cases. The effect
of these protective haplotypes was consistent across sample sets
(OR.sub.SS1=0.66, OR.sub.SS2=0.67, OR.sub.SS3=0.69), and the
combined analysis was rather significant (P.sub.MH=4.32E-07).
Importantly, the level of heterogeneity of effect was not
significant across sample sets for the protective haplotype
grouping of TTAGT and CGGAA versus all other haplotypes
(P.sub.Het=0.961) as determined from the Mantel-Haenszel procedure
to test odds ratios for homogeneity (see the "Materials and
Methods" section of Example 1 below).
[0514] All possible combinations of these five SNPs were then
systematically evaluated in an exploratory analysis to see if one
or more of these SNPs could be eliminated while retaining or
increasing the significance of the association result. Eliminating
rs11465804 and rs1857292 from the haplotypes yielded a simpler,
slightly stronger association result for the protective haplotypes
(TAG and CGA vs. Others; P.sub.MH=3.88E-08) (Table 6) (although
stochastic effects may not be ruled out). Without these two SNPs,
the frequencies of the resulting protective haplotypes increased to
20% in controls and 14% in cases.
[0515] To better understand the physical extent of the protective
haplotypes in this region, the haplotype analysis was expanded to
include all contiguous markers such that the association signal was
not substantially diminished by estimated historical recombination
events. This region appeared to extend 55 kb from P310L through the
3' region of IL23R to rs11209032 in the IL23R-IL12RB2 intergenic
region. Haplotype analysis was performed on all twenty-three
markers in this region (Table 7). Again, two common protective
haplotypes were identified. Although the initial five- and
three-marker protective haplotypes described above did not share
alleles at any sites, the two protective haplotypes from the
twenty-three marker analysis had twelve markers with the same
alleles on both haplotypes. As no other common (>1%) haplotypes
shared the alleles at these twelve markers, the analysis was
reduced to those twelve markers and another haplotype analysis was
carried out (Table 8). Notably, the protective haplotype from this
reduced set of SNPs, AGTTCCTCCCAG, carries substantial effects
(freq in cases=12%, freq in controls=17%; OR.sub.MH=0.68;
P.sub.MH=3.18E-07) and does not include P310L, R381Q or SNPs in
high LD with these two missense SNPs (rs10889671, rs1857292, or
rs11465804). In addition, this haplotype is remarkably similar in
frequency and effect size across all three sample sets (in the case
for the three marker haplotype rs7530511-rs10889671-rs11209026
described previously, the TAG haplotype exhibited the strongest
protective effects in the Utah population-derived Sample Set 1
while the CGA haplotype was stronger in the remaining two sample
sets which were derived from the North American white population in
general).
[0516] To determine whether or not this 12-marker haplotype
represents a variant contributing to psoriasis association
independently of P310L and R381Q, the 12-marker haplotypes were
dichotomized into the protective haplotype described above and an
aggregate of all other haplotypes, and then the same was done for
the rs7530511-rs11209026 haplotypes (TG and CA protective
haplotypes combined together vs. CG and TA combined together). A
diplotype-based, squared correlation coefficient r.sup.2 statistic
was then calculated between the two haplotype groupings. All
individuals were used across all sample sets for this calculation.
The resulting value, r.sup.2=0.78, indicated a fairly high degree
of correlation between the two diplotype groupings, thereby
suggesting that although they were not completely redundant, these
were not independent effects.
[0517] The LD patterns and haplotype results appear to indicate
that more than one polymorphism is contributing to the psoriasis
association linked to IL23R. To formally investigate this, a test
of conditional association was performed on SNPs having the most
significant combined P-values (P<0.005) for the 2df genotype
test and exhibiting significant Mantel-Haenzsel confidence
intervals (95% CI excluding 1.0) for the allelic OR jointly
calculated over the three sample sets. As some of these SNPs
clustered into "LD groups" consisting of SNPs in very high LD and
similar statistical significance for psoriasis association, a
representative SNP was selected from each LD group when
appropriate. Six SNPs met these criteria: the missense SNPs
rs7520511 (P310L) and rs11209026 (R381Q), rs10889674 (putative
transcription factor binding site, intron 9 IL23R), rs1857292 (3'
of IL23R), rs11465804 (intron 8 of IL23R) and rs10889671 (intron 8
IL23R). Rs11465804 and rs10889671 were excluded from this analysis
due to high LD with one of the missense SNPs (rs10889671-rs7530511
r.sup.2=0.943; rs11465804-rs11209026 r.sup.2=0.852) and since both
missense SNPs had slightly elevated significance when compared to
these LD counterparts. The conditional association permutation test
revealed that the genotype association at R381Q remained
significant after fixing the genotypes at P310L
(P.sub.comb=0.00031), or either of the remaining two SNPs
(P.sub.comb=0.0183, fixing genotypes at rs10889674;
P.sub.comb=0.0027, fixing genotypes at rs1857292). Conversely, the
genotype association at P310L was also significant, albeit mildly
so, following conditioning on R381Q genotypes (P.sub.comb=0.0299);
however the moderate LD between P310L and the other two SNPs
removed the association at P310L. These results for the mutually
conditionally independent association of the two missense SNPs were
not unexpected given the very low amount of LD between these two
SNPs. Hence, there is some evidence of at least two IL23R-linked
polymorphisms independently contributing to psoriasis.
[0518] As other SNPs, not genotyped in this study, could possibly
drive the association results observed here, the HapMap LD results
were investigated for the CEU samples between genomic positions
67,225,114-67,725,113 on Build36..sup.35 Examining four key SNPs
from this study, rs7530511, rs10889671, rs11465804, and rs11209026,
seven SNPs were found to be in substantial LD (r.sup.2>0.50)
with either rs7530511, rs10889671 or both: rs2863212 (IL23R intron
6), rs7528924 (IL23R intron 7), rs4655692 (IL23R intron 7),
rs4655693 (IL23R intron 7), rs11804284 (IL23R intron 7), rs4655530
(IL23R intron 8), and rs2863209 (intragenic, within 8 kb 3' of
IL23R). The remaining two SNPs were only in substantial LD with
each other (r.sup.2.sub.rs11465804-rs11209026=0.852).
[0519] Discussion
[0520] Fine mapping of the IL23R-linked region shows variants
segregating at IL23R coding and flanking regions significantly
associated with psoriasis. In particular, there are extended
haplotypes in this region that protect against psoriasis
susceptibility. Importantly, it also appears that at least two
IL23R polymorphisms, P310L and R381Q, independently contribute to
linkage disequilibrium with the psoriasis phenotype. In addition,
both sliding window haplotype analyses and longer-range haplotype
work pinpointed the association signal to the IL23R coding region.
This is particularly important as the interleukin 12 receptor
subunit-encoding gene, IL12RB2, is located 47 kb from the 3' end of
IL23R and some SNP pairs exhibit substantial and even perfect
linkage disequilibrium between sites located in the coding regions
of the two genes (as determined by genotyping in the CEU HapMap
samples). Recent animal studies show that the IL12RB2 knockout
mouse develops an autoimmune/lymphoproliferative disorder with
aberrant IL-12 signaling..sup.36 Hence, IL12RB2 is a reasonable
psoriasis candidate gene. However, the genetic results presented
here seriously diminish the possibility that IL12RB2 alleles are
primarily responsible for the observed psoriasis predisposing
effects.
[0521] The HapMap project has general population genotype data on
both missense SNPs, rs7530511 (P310L) and rs11209026
(R381Q)..sup.35 At rs11209026, the A allele (minor allele) was
found on CEU and YRI chromosomes (8 out of 120 CEU chromosomes and
2 out of 120 YRI chromosomes), but not on chromosomes from the two
East Asian samples (CHB and JPT). Hence, it is possible that
rs11209026 may predispose some African and/or African-derived
populations to autoimmunity and autoinflammatory traits,
particularly if the effect size is larger in those subpopulations
than European-derived samples. The rs7530511 SNP is polymorphic in
all four HapMap sample sets, with varying frequencies: 15/120 CEU
chromosomes, 2/90 CHB chromosomes, 3/88 JPT chromosomes, and 35/118
YRI chromosomes; thereby suggesting that the autoinflammatory
effects ascribed to P310L for the North American white samples
might translate to these other populations. For each of these SNPs,
the minor allele in humans appears to be derived, as many
vertebrates including the chimpanzee, macaque, mouse, rat, cow, dog
and chicken carry the major allele nucleotides at the orthologous
sites.
[0522] These genetic findings coupled with results from multiple
areas of research ranging from molecular immunology to clinical
biology implicate the IL-23/T.sub.H-17 pathway as being central to
chronic inflammatory conditions such as psoriasis and inflammatory
bowel disease; the perturbation of which may disrupt the
communication between the innate and adaptive immune responses. In
sum, these studies demonstrate several key aspects of
IL-23/T.sub.H-17 pathobiology related to psoriasis: 1) Both
IL-12p40 and IL-23p19 mRNA expression levels are significantly
elevated in both non-lesional psoriatic skin versus normal skin as
well as lesional psoriatic skin versus non-lesional psoriatic
skin..sup.37,38 2) IL-12 and IL-23 knockouts and IL23-deficient
animal model experiments indicate that the systemic inflammatory
effects, dermal inflammation and epidermal hyperplasia are often
mediated through the IL-23/T.sub.H-17 pathway.sup.38,39, 3)
T.sub.H17 survival and expansion, key characteristics of epithelial
inflammation and epidermal hyperplasia, occur in response to
IL-23.sup.40-42 4) IL-23p19 antibodies inhibit proinflammatory
cytokines in a mouse model of IBD.sup.43, and 5) clinical studies
have shown dramatic efficacy of IL-12p40 antibodies in reducing
symptoms in a high percentage of psoriatic subjects.sup.44,45 and
those with active Crohn's disease..sup.46 These diverse studies
have conspired to highlight the central function of the
IL-23/T.sub.H-17 axis in mediating chronic inflammatory disease
pathogenesis, downplaying the role of IL-12. Hence, full genetic
description of both IL12B and IL23R, genes encoding for critical
proteins in the IL-23/T.sub.H-17 response, enables delineation of
specific variants predisposing and protective of disease and
facilitates a further understanding of the molecular pathobiology
of autoinflammatory phenotypes.
[0523] Along with psoriasis, IL23R appears to play an important
role in predisposition to other autoinflammatory diseases including
IBD (particularly adult and pediatric Crohn's disease).sup.16-24,
AS.sup.25,26, and GO..sup.27 IL23R variants may also underlie
susceptibility to celiac disease.sup.28, Graves' disease without
ophthalmopathy.sup.27 and multiple sclerosis.sup.25,28,29,30,31
Interestingly, multiple independent IL23R polymorphisms have been
reported to be associated with AS, GO and Crohn's disease,
suggesting a model of allelic heterogeneity within each disease
where disruption of IL-23R function can occur from several distinct
genetic insults. With AS, both R381Q and rs1343151 are replicated
SNPs (R381Q was associated with psoriasis in this study). Two IL23R
SNPs, rs2201841 and rs10889677, are associated with GO, and P310L
may be associated with Graves' disease. R381Q may be the major
IL23R susceptibility polymorphism for Crohn's disease with the
minor allele conferring protective effects as in psoriasis.
rs7517847 plays a role in Crohn's disease, and P310L appears to be
significantly correlated with psoriasis.
[0524] The IL23R variants described herein have uses related to
targeted therapeutics, such as the efficacious IL12/23 monoclonal
antibodies.sup.44-46, and in autoinflammatory pharmacogenetics, for
example.
[0525] Materials and Methods
[0526] Subjects
[0527] The subjects in all three sample sets were white North
American individuals. Sample Set 1 (also referred to herein as
"S0048") consisted of 467 psoriasis cases and 500 controls, all
residing in either Utah or southern Idaho. Sample Set 2 (also
referred to herein as "50056A") was obtained by the Genomics
Collaborative Division of SeraCare Life Sciences (GCI) and included
498 cases and 498 controls. Lastly, BioCollections Worldwide and
GCI provided Sample Set 3 (also referred to herein as "A0019"),
composed of 481 cases and 424 controls. Details concerning these
subjects were previously described..sup.11 All individuals included
in this study were 18 years or older at time of enrollment. All
protocols were approved by national and/or local institutional
review boards, and informed written consent was obtained from all
subjects.
[0528] Genotyping
[0529] Individual genotyping was performed using allele-specific
kinetic PCR on 0.3 ng of DNA and the resulting data hand-curated
prior to statistical analyses without knowledge of case/control
status. Genotyping accuracy of the laboratory is consistently
better than 99%..sup.11
[0530] SNP Selection
[0531] A multifaceted approach was undertaken to identify SNPs to
genotype individually in a fine-scale mapping effort in the IL23R
region. A 336 kbp region was selected across a portion of C1orf141
through SERBP1. This region was delineated on the basis of two
criteria: 1) the decay of LD from the two IL23R SNPs, rs7530511 and
rs11209026, originally identified to be associated in the sample
sets.sup.11, and 2) coverage of clear biological candidate genes
nearby--in this case, IL23R and IL12RB2. Next, SNPs were selected
in this 336 kbp region to cover two genetic models: one of allelic
heterogeneity where multiple variants segregating at the same gene
or functional motif independently contribute to disease
predisposition; and the second model where the association observed
at the originally-identified SNPs, rs7530511 and rs11209026, was
driven through LD with one or more untyped polymorphisms. To
address these two possible models, SNPs were partitioned in the 336
kbp region into those in moderate to high LD (r.sup.2>0.20) with
one of the original two associated SNPs, and those exhibiting weak
LD with the original SNPs (r.sup.2<0.20). The threshold value of
r.sup.2=0.20 was determined analytically by solving for the r.sup.2
value that would generate the observed results at these two
original SNPs from an untyped marker having a reasonable disease
model (relative risk below 2.25 with similar allele frequency). The
r.sup.2 values were calculated from the HapMap CEU data..sup.35
Next, the tagging SNP program Redigo.sup.47 was ran on those SNPs
in weak LD, selecting SNPs with the highest power to detect an
arbitrary disease predisposing site in the region. Redigo uses a
genotype-based approach that maximizes power to detect disease
susceptibility SNPs. All of the SNPs in the moderate-to-high LD
group were then selected and this set was reduced so that SNPs in
extremely high LD (r.sup.2>0.97) were represented by a single
SNP. Lastly, any SNP with putative functional annotation was
selected to be genotyped. In all, 61 SNPs, inclusive of the two
SNPs fully genotyped in the original study, were identified and
judged as being sufficient to cover both genetic models for the
IL23R region.
[0532] Statistical Analysis
[0533] Several analyses were performed on individual SNPs. An
in-house genetic analysis application was used to analyze much of
the data. Hardy-Weinberg equilibrium testing was accomplished
through the exact test of Weir..sup.48 A William's-corrected G-test
was used to calculate P-values for genotypic association..sup.49
Approximate confidence intervals for the odds ratios were
calculated using the typical estimate of the standard error of the
log-odds ratio. The Mantel-Haenszel procedure to test odds ratios
for homogeneity (test of heterogeneity of effect) was performed
following Sokal and Rohlf (Chapter 17, Reference 49). P-values were
combined across sample sets using either the continuity-corrected
Mantel-Haenszel statistic (eqn 17.22, reference 49) or the Fisher's
combined P-value (omnibus procedure)..sup.50 Similarly,
Mantel-Haenszel common odds ratios were calculated to combine data
across sample sets..sup.51 A Monte Carlo simulation was written in
XLISP-STAT to calculate 95% confidence intervals on the common odds
ratios. Typically, 20,000 iterations of the Monte Carlo were
performed unless results were not sufficiently converging, in which
case 40,000 iterations were used.
[0534] Pairwise linkage disequilibrium was calculated using either
the LDMax package where 2-SNP haplotypes were estimated through an
EM algorithm and the standard r.sup.2 statistic employed,.sup.52,53
or, in some instances, an r.sup.2 statistic was calculated using
unphased genotype or diplotype data. Given perfect phasing for the
double heterozygotes and Hardy-Weinberg Equilibrium, these two
methods yield identical values.
[0535] Sliding window haplotype association tests were performed by
running Haplo.Stats.sup.54 sequentially on adjacent sets of three
SNPs. Plots of the global P-values from each window were plotted
against the average position of the SNPs in the window. Additional
haplotype and diplotype work was performed using the Pseudo-Gibbs
sampling algorithm from the SNPAnalyzer program.sup.55 to estimate
phase, followed by a William's-corrected G test of homogeneity.
[0536] Similar to the haplotype method.sup.56, a test of pairwise
conditional independence (i.e., fixing the genotypes at one SNP and
testing for the association at a second SNP) was performed through
a permutation routine where case/control status is permuted against
genotype data to generate a null distribution. For conditional
independence hypotheses concerning only a small number of highly
significant SNPs driving correlated SNPs to association solely
through LD (such as is the case here), a permutation method has
advantages over logistic regression models in that the P-values,
given a sufficient number of iterations, will be appropriate
regardless of LD levels, effect size and counts. Alternatively,
logistic regression-based methods are preferred in situations that
warrant inclusion of many SNPs and/or covariates with low to
moderate LD/correlation levels and/or the hypothesis tested
requires adjustment to be performed on more than one SNP.
Typically, 2,000 iterations of the permutation were performed and
P-values were calculated through a modeling procedure where a
log-likelihood ratio test statistic is calculated for each of the
permuted iterations. Next, the parameters of a gamma probability
density are estimated from the permuted log-likelihood ratio test
statistics and a P-value is calculated by integrating this null
density from the observed log-likelihood ratio statistic. For a
given number of permutation iterations, this modeling procedure
gives more accurate P-values than simply taking the frequency of
those permuted iterations that exceed the observed value.
[0537] Related Material Incorporated Herein by Reference
[0538] Garcia et al., "Detailed genetic characterization of the
interleukin-23 receptor in psoriasis", Genes Immun. 2008 September;
9(6):546-55; U.S. patent application Ser. No. 11/899,017, filed
Aug. 31, 2007 (Begovich et al.); and Cargill et al., "A large-scale
genetic association study confirms IL12B and leads to the
identification of IL23R as psoriasis risk genes", Am J Hum Genet.
2007 February; 80(2):273-90, which describe the same sample sets as
used here in Example 1, are each incorporated herein by reference
in their entirety.
REFERENCES
[0539] 1. Chan J R, Blumenschein W, Murphy E, Diveu C, Wiekowski M,
Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF
and IL-20R2-dependent mechanisms with implications for psoriasis
pathogenesis. J Exp Med 2006; 203:2577-2587. [0540] 2. Neimann A L,
Porter S B, Gelfand J M. The epidemiology of psoriasis. Expert Rev
Dermatol 2006; 1: 63-75. [0541] 3. Kremers H M, McEvoy M T, Dann F
J, Gabriel S E. Heart disease in psoriasis. J Am Acad Dermatol
2007; 57:347-354. [0542] 4. Griffiths C E M, Barker J N
Pathogenesis and clinical features of psoriasis. The Lancet 2007;
370:263-271. [0543] 5. Farber E M, Nall M L, Watson W. Arch
Dermatol 1974; 109:207-211. [0544] 6. Nair R P, Stuart P E, Nistor
I, Hiremagalore R, Chia N V, Jenisch S et al. Sequence and
haplotype analysis supports HLA-C as the psoriasis susceptibility 1
gene. Am J Hum Genet 2006; 78:827-851. [0545] 7. Helms C, Cao L,
Krueger J G, Wijsman E M, Chamain F, Gordon D, et al. A putative
RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated
with susceptibility to psoriasis. 2003; Nat Genet 35:349-356.
[0546] 8. Capon F, Helms C, Veal C D, Tillman D, Burden A D, Barker
J N, et al. Genetic analysis of PSORS2 markers in a UK dataset
supports the association between RAPTOR SNPs and familial
psoriasis. 2004; J Med Genet 41:459-460. [0547] 9. Stewart P, Nair
R P, Abecasis G R, Nistor I, Hiremagalore R, Chia N V, et al.
Analysis of RUNX1 binding site and RAPTOR polymorphisms in
psoriasis: no evidence for association despite adequate power and
evidence for linkage. 2006; J Med Genet 43:12-17. [0548] 10.
Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Fujita H, et al.
Interleukin-12 p40 gene (IL12B) 3'-untranslated region polymorphism
is associated with susceptibility to atopic dermatitis and
psoriasis vulgaris. J Dermatol Sci 2002; 302:161-166. [0549] 11.
Cargill M, Schrodi S J, Chang M, Garcia V E, Brandon R, Callis K P,
et al. A large-scale genetic association study confirms IL12B and
leads to the identification of IL23R as psoriasis-risk genes. Am J
Hum Genet 2007; 80:273-290. [0550] 12. Capon F, DiMeglio P, Szaub
J, Prescott N J, Dunster C, Baumber L, et al. Sequence variants in
the genes for the interleukin-23 receptor (IL23R) and its ligand
(IL12B) confer protection against psoriasis. Hum Genet 2007;
122:201-206.
[0551] 13. Smith R L, Warren R B, Eyre S, Ho P, Ke X, Young H S, et
al. Polymorphisms in the IL-12beta and IL-23R genes are associated
with psoriasis of early onset in a UK cohort. J Invest Dermatol
2007; Nov. 22 [Epub ahead of print] [0552] 14. Nair R P, Ruether A,
Stuart P E, Jenisch S, Tejasvi T, Hiremagalore R, et al.
Polymorphisms of the IL12B and IL23R genes are associated with
psoriasis. J Invest Dermatol 2008; Jan. 24 [Epub ahead of print].
[0553] 15. Liu Y, Helms C, Liao W, Zaba L C, Duan S, Gardner J, et
al. A genome-wide association study of psoriasis and psoriatic
arthritis identifies new disease loci. PLoS Genet. 2008;
28:e1000041. [0554] 16. Duerr R H, Taylor K D, Brant S R, Rioux J
D, Silverberg M S, Daly M J, et al. A genome-wide association study
identifies IL23R as an inflammatory bowel disease gene. Science
2006; 314:1461-1463. [0555] 17. Libioulle C, Louis E, Hansoul S,
Sandor C, Farnir F, Franchimont D, et al. Novel Crohn disease locus
identified by genome-wide association maps to a gene desert on
5p13.1 and modulates expression of PTGER4. PLoS Genet. 2007; 3:e58.
[0556] 18. Wellcome Trust Case Control Consortium. Genome-wide
association study of 14,000 cases of seven common diseases and
3,000 shared controls. Nature 2007; 447:661-678. [0557] 19. Parkes
M, Barrett J C, Prescott N J, Tremelling M, Anderson C A, Fisher S
A, et al. Sequence variants in the autophagy gene IRGM and multiple
other replicating loci contribute to Crohn's disease
susceptibility. Nat Genet. 2007; 39:830-832. [0558] 20. Raelson J
V, Little R D, Ruether A, Fournier H, Paquin B, Van Eerdewegh, et
al. Genome-wide association study for Crohn's disease in the Quebec
founder population identifies multiple validated disease loci. Proc
Natl Acad Sci USA. 2007; 104:14747-14752. [0559] 21. Tremelling M,
Cummings F, Fisher S A, Mansfield J, Gwilliam R, Keniry A, et al.
IL23R variation determines susceptibility but not disease phenotype
in inflammatory bowel disease. Gastroenterology 2007;
132:1657-1664. [0560] 22. Van Limbergen J, Russell R K, Nimmo E R,
Drummond H E, Smith L, Davies G, et al. IL23R Arg381Gln is
associated with childhood onset inflammatory bowel disease in
Scotland. Gut 2007; 56:1173-1174. [0561] 23. Dubinsky M C, Wang D,
Picornell Y, Wrobel I, Katzir L, Quiros A, et al. IL-23 receptor
(IL-23R) gene protects against pediatric Crohn's disease. Inflamm
Bowel Dis 2007; 13:511-515. [0562] 24. Baldassano R N, Bradfield J
P, Monos D S, Kim C E, Glessner J T, Casalunovo T, et al.
Association of variants of the interleukin-23 receptor gene with
susceptibility to pediatric Crohn's disease. Clin Gastroenterol
Hepatol 2007; 5:972-976. [0563] 25. Wellcome Trust Case Control
Consortium, Australo-Anglo-American Spondylitis Consortium (TASC),
Burton P R, Clayton D G, Cardon L R, Craddock N, et al. Association
scan of 14,500 nonsynonymous SNPs in four diseases identifies
autoimmunity variants. Nat Genet. 2007; 39:1329-1337. [0564] 26.
Rueda B, Orozco G, Raya E, Fernandez-Sueiro J L, Mulero J, Blanco F
J, et al. The IL23R Arg381R non-synonymous polymorphism confers
susceptibility to ankylosing spondylitis. Ann Rheum Dis. 2008; Jan.
16 [Epub ahead of print]. [0565] 27. Huber A K, Jacobson E M,
Jazdzewski K, Concepcion E S, Tomer Y. IL-23R is a major
susceptibility gene for Graves' ophthalmopathy: the IL-23/Th17 axis
extends to thyroid autoimmunity. J Clin Endocrinol Metab 2007;
93:1077-1081. [0566] 28. Nunez C, Dema B, Cenit M C, Polanco I,
Maluenda C, Arroyo R, et al. IL23R: a susceptibility locus for
celiac disease and multiple sclerosis? Genes Immun. 2008; March 27
[Epub ahead of print]. [0567] 29. Illes Z, Safrany E, Peterfalvi A,
Magyari L, Farago B, Pozsonyi E, et al. 3'UTR C2370A allele of the
IL-23 receptor gene is associated with relapsing-remitting multiple
sclerosis. Neurosci Lett. 2008; 431:36-38. [0568] 30. Roos I M,
Kockum I, Hillert J. The interleukin 23 receptor gene in multiple
sclerosis: a case-control study. J Neuroimmunol. 2008; 194:173-180.
[0569] 31. Begovich A B, Chang M, Caillier S J, Lew D, Catanese J
J, Wang J, et al. The autoimmune disease-associated IL12B and IL23R
polymorphisms in multiple sclerosis. Hum Immunol. 2007; 68:934-937.
[0570] 32. Zhang X-J, Yan K-L, Wang Z-M, Yang S, Zhang G-L, Fan X,
et al. Polymorphisms in interleukin-15 gene on chromosome 4q31.2
are associated with psoriasis vulgaris in Chinese population. J
Invest Derm 2007; 127:2544-2551. [0571] 33. Chang M, Li Y, Yan C,
Duffin K P C, Matsunami N, Garcia V E, et al. Variants in the 5q31
cytokine gene cluster are associated with psoriasis. Genes Immun
2007; 9:176-181. [0572] 34. Clark A G. The role of haplotypes in
candidate gene studies. Genet Epidemiol 2004; 27:321-333. [0573]
35. International HapMap Consortium. A haplotype map of the human
genome. Nature 2007; 437:1299-1320. [0574] 36. Airoldi I, Di Carlo
E, Cocco C, Sorrentino C, Fais F, Cilli M, et al. Lack of i112rb2
signaling predisposes to spontaneous autoimmunity and malignancy.
Blood 2005; 106:3846-3853. [0575] 37. Lee E, Trepicchio W L,
Oestreicher J L, Pittman D, Wang F, Chamian F, et al. Increased
expression of interleukin 23 p19 and p40 in lesional skin of
patients with psoriasis vulgaris. J Exp Med 2004; 199:125-130.
[0576] 38. Chan J R, Blumenschein W, Murphy E, Diveu C, Wiekowski
M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via
TNF and IL-20R2-dependent mechanisms with implications for
psoriasis pathogenesis. J Exp Med 2006; 203:2577-2587. [0577] 39.
Ghilardi N, Kljavin N, Chen Q, Lucas S, Gurney A L, de Sauvage F J.
Compromised humoral and delayed-type hypersensitivity responses in
IL-23-deficient mice. J Immunol 2004; 172:2827-2833. [0578] 40.
Park H, Li Z, Yang X O, Chang S H, Nurieva R, Wang Y H, et al. A
distinct lineage of CD4 T cells regulates tissue inflammation by
producing interleukin 17. Nat Immunol 2005; 6:1133-1141. [0579] 41.
Harrington L E, Hatton R D, Mangan P R, Turner H, Murphy T L,
Murphy K M, et al. Interleukin 17-producing CD4+ effector T cells
develop via a lineage distinct from the T helper type 1 and 2
lineages. Nat Immunol 2005; 6:1123-1132. [0580] 42. Veldhoen M,
Hocking R J, Atkins C J, Locksley R M, Stockinger B. TGF.beta. in
the context of an inflammatory cytokine milieu supports de novo
differentiation of IL-17-producing T-cells. Immunity 2006;
24:179-189. [0581] 43. Hue S, Ahern P. Buonocore S, Kullberg M C,
Cua D J, McKenzie B S, et al. Interleukin-23 drives innate and T
cell-mediated intestinal inflammation. J Exp Med 2006;
203:2473-2483. [0582] 44. Kauffman C L, Aria N, Toichi E, McCormick
T S, Cooper K D, Gottlieb A B, et al. A phase I study evaluating
the safety, pharmacokinetics, and clinical response of a human
IL-12 p40 antibody in subjects with plaque psoriasis. J Invest
Dermatol 2004; 123:1037-1044. [0583] 45. Krueger G G, Langley R G,
Leonardi C, Yeilding N, Guzzo C, Wang Y, et al. A human
interleukin-12/23 monoclonal antibody for the treatment of
psoriasis. N Engl J Med 2007; 356:580-592. [0584] 46. Mannon P J,
Fuss I J, Mayer L, Elson C O, Sandborn W J, Present D, et al.
Anti-interleukin-12 antibody for active Crohn's disease. N Engl J
Med 2004; 351:2069-2079. [0585] 47. Hu X, Schrodi S J, Ross D A,
Cargill M. Selecting tagging SNPs for association studies using
power calculations from genotype data. Hum Hered 2004; 57:156-170.
[0586] 48. Weir B S. Genetic Data Analysis II: Methods for Discrete
Population Genetic Data. 1996; Sinauer, Sunderland, Mass., USA.
[0587] 49. Sokal R R, Rohlf F J. Biometry 3.sup.rd ed. 1995; W.H.
Freeman and Company, USA. [0588] 50. Fisher R A. Statistical
Methods for Research Workers, 12.sup.th ed. 1954; Oliver &
Boyd, Edinburgh. [0589] 51. Mantel N, Haenszel W. Statistical
aspects of the analysis of data from retrospective studies of
disease. J Nat Cancer Inst. 1959; 22:719-748. [0590] 52. Excoffier
L, Slatkin M. Maximum-likelihood estimation of molecular haplotype
frequencies in a diploid population. Mol Biol Evol 1995;
12:921-927. [0591] 53. Abecasis G R, Cookson W O. GOLD--graphical
overview of linkage disequilibrium. Bioinformatics 2000;
16:182-183. [0592] 54. Schaid D J, Rowland C M, Tines D E, Jacobson
R M, Poland G A. Score tests for association between traits and
haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002;
70:425-434. [0593] 55. Yoo J, Seo B, Kim Y. SNPAnalyzer: a
web-based integrated workbench for single-nucleotide polymorphism
analysis. Nucleic Acids Res 2005; 33(Web Server issue): W483-488.
[0594] 56. Li H. A permutation procedure for the haplotype method
for identification of disease-predisposing variants. Ann Hum Genet
2001; 65:189-196.
Example 2
Identification and Analysis of Haplotypes and Individual SNPs in
the IL12B Region Associated with Psoriasis
[0595] IL12B Haplotypes
[0596] Using the same sample sets as described above in Example 1
for the IL23R region, haplotype analyses were carried out to
identify SNP haplotypes in the IL12B region that are associated
with psoriasis risk.
[0597] The sample sets (psoriasis case and control samples) used
for the haplotype analyses of the IL12B region are described in
Example 1 above ("S0048", "50056A", and "A0019" as indicated in
Tables 9-10 correspond to "Sample Set 1", "Sample Set 2", and
"Sample Set 3", respectively, which are described above in Example
1). The sample sets are also the same as those described in U.S.
patent application Ser. No. 11/899,017, filed Aug. 31, 2007
(Begovich et al.), and Cargill et al., "A large-scale genetic
association study confirms IL12B and leads to the identification of
IL23R as psoriasis risk genes", Am J Hum Genet. 2007 February;
80(2):273-90, both of which are incorporated herein by reference in
their entirety.
[0598] Methods were similar to those described above in Example 1,
and in U.S. patent application Ser. No. 11/899,017, filed Aug. 31,
2007 (Begovich et al.), and Cargill et al., "A large-scale genetic
association study confirms IL12B and leads to the identification of
IL23R as psoriasis risk genes", Am J Hum Genet. 2007 February;
80(2):273-90, both of which are incorporated herein by reference in
their entirety.
[0599] For haplotype analyses, the Haplo.Stats program using an EM
algorithm (Schaid et al., "Score tests for association between
traits and haplotypes when linkage phase is ambiguous", Am J Hum
Genet 2002; 70:425-434) and the SNP Analyzer program using a
pseudo-Gibbs sampling algorithm (Yoo et al., "SNPAnalyzer: a
web-based integrated workbench for single-nucleotide polymorphism
analysis", Nucleic Acids Res 2005; 33: W483-488) were used.
[0600] The results of these analyses are shown in Tables 9 and
10.
[0601] As shown in Tables 9 and 10, the following haplotypes were
identified in particular as non-risk (protective) haplotypes for
psoriasis:
[0602] 1) rs2546892 (G), rs1433048 (A), rs6894567 (G), rs17860508
(C), rs7709212 (C), rs953861 (A), rs6869411 (T), rs1833754 (T), and
rs6861600 (G) (naive odds ratio=0.594); and
[0603] 2) rs1368437 (C), rs2082412 (A), rs7730390 (C), rs3181225
(G), rs1368439 (T), rs3212227 (G), rs3213120 (C), rs3213119 (G),
and rs2853696 (C) (naive odds ratio=0.639).
[0604] As shown in Table 10, the following haplotypes were
identified in particular as psoriasis risk (susceptibility)
haplotypes:
[0605] 1) rs1368437 (C), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (G), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (T) (naive odds ratio=1.241); and
[0606] 2) rs1368437 (G), rs2082412 (G), rs7730390 (T), rs3181225
(G), rs1368439 (T), rs3212227 (T), rs3213120 (C), rs3213119 (G),
and rs2853696 (C) (naive odds ratio=1.346).
[0607] Individual IL12B SNPs
[0608] In addition to haplotype analysis, analysis of individual
SNPs in the IL12B region for association with psoriasis risk was
also carried out using the same sample sets (i.e., the sample sets
described in Example 1 above and in Cargill et al., "A large-scale
genetic association study confirms IL12B and leads to the
identification of IL23R as psoriasis risk genes", Am J Hum Genet.
2007 February; 80(2):273-90, as well as in patent application Ser.
No. 11/899,017, filed Aug. 31, 2007 (Begovich et al.)). In summary,
the combined sample sets used in this analysis totaled 1,448
individuals with dermatologist-confirmed psoriasis (cases) and
1,385 "normal" subjects without psoriasis (controls) (these totals
included three independent white, North American psoriasis sample
sets, as follows: Sample Set 1 (obtained from the University of
Utah) consisted of 467 cases and 460 controls, Sample Set 2
(obtained from the Genomics Collaborative Division of SeraCare Life
Sciences) consisted of 498 cases and 498 controls, and Sample Set 3
(obtained from Genomics Collaborative and BioCollections Worldwide)
consisted of 483 cases and 427 control subjects).
[0609] 105 SNPs were identified as being associated with psoriasis
risk (p-value<0.05), and these SNPs are shown in Table 11. Of
these 105 SNPs, the association of 29 of these SNPs with psoriasis
was identified by genotyping of the psoriasis sample sets (using
the combined total of 1,448 cases and 1,385 controls) and the
association of the other 76 SNPs with psoriasis was identified
based on imputation. This is indicated in Table 11, in which the
column labeled "Genotyped or Imputed" indicates whether the data
provided for the given SNP was derived from genotyping of the
psoriasis sample sets or by imputation.
[0610] Imputation was carried out using the BEAGLE genetic analysis
program to analyze genotyping data from the HapMap project (The
International HapMap Consortium). Imputation and the BEAGLE program
(including the modeling algorithm that BEAGLE utilizes) are
described in the following references: Browning, "Missing data
imputation and haplotype phase inference for genome-wide
association studies", Hum Genet (2008) 124:439-450 (which reviews
imputation and BEAGLE); B L Browning and S R Browning (2009) "A
unified approach to genotype imputation and haplotype phase
inference for large data sets of trios and unrelated individuals".
Am J Hum Genet 84:210-223 (which describes BEAGLE's methods for
imputing ungenotyped markers and phasing parent-offspring trios); S
R Browning and B L Browning (2007) "Rapid and accurate haplotype
phasing and missing data inference for whole genome association
studies using localized haplotype clustering". Am J Hum Genet
81:1084-1097 (which describes BEAGLE's methods for inferring
haplotype phase or sporadic missing data in unrelated individuals);
B L Browning and S R Browning (2007) "Efficient multilocus
association mapping for whole genome association studies using
localized haplotype clustering". Genet Epidemiol 31:365-375 (which
describes BEAGLE's methods for association testing); S R Browning
(2006) "Multilocus association mapping using variable-length Markov
chains". Am J Hum Genet 78:903-13 (which describes BEAGLE's
haplotype frequency model); and B L Browning and S R Browning
(2008) "Haplotypic analysis of Wellcome Trust Case Control
Consortium data". Human Genetics 123:273-280 (which describes an
example in which BEAGLE was used to analyze a large genome-wide
association study). Each of these references related to imputation
and the BEAGLE program is incorporated herein by reference.
Example 3
LD SNPs Associated with Autoinflammatory Diseases
[0611] Another investigation was conducted to identify additional
SNPs that are calculated to be in linkage disequilibrium (LD) with
certain "interrogated SNPs" that have been found to be associated
with autoinflammatory diseases, particularly psoriasis, as
described herein and shown in the tables. The interrogated SNPs are
shown in column 1 (which indicates the hCV identification numbers
of each interrogated SNP) and column 2 (which indicates the public
rs identification numbers of each interrogated SNP) of Table 4. The
methodology is described earlier in the instant application. To
summarize briefly, the power threshold (T) was set at an
appropriate level, such as 51%, for detecting disease association
using LD markers. This power threshold is based on equation (31)
above, which incorporates allele frequency data from previous
disease association studies, the predicted error rate for not
detecting truly disease-associated markers, and a significance
level of 0.05. Using this power calculation and the sample size, a
threshold level of LD, or r.sup.2 value, was derived for each
interrogated SNP (r.sub.T2, equations (32) and (33) above). The
threshold value r.sub.T2 is the minimum value of linkage
disequilibrium between the interrogated SNP and its LD SNPs
possible such that the non-interrogated SNP still retains a power
greater or equal to T for detecting disease association.
[0612] Based on the above methodology, LD SNPs were found for the
interrogated SNPs. Several exemplary LD SNPs for the interrogated
SNPs are listed in Table 4; each LD SNP is associated with its
respective interrogated SNP. Also shown are the public SNP IDs (rs
numbers) for the interrogated and LD SNPs, when available, and the
threshold r.sup.2 value and the power used to determine this, and
the r.sup.2 value of linkage disequilibrium between the
interrogated SNP and its corresponding LD SNP. As an example in
Table 4, the interrogated SNP rs10889677 (hCV11283764) was
calculated to be in LD with rs2201841 (hCV1272302) at an r.sup.2
value of 0.9325, based on a 51% power calculation, thus also
establishing the latter SNP as a marker associated with psoriasis
(as well as related pathologies such as Crohn's disease).
[0613] In general, the threshold r.sub.T2 value can be set such
that one of ordinary skill in the art would consider that any two
SNPs having an r.sup.2 value greater than or equal to the threshold
r.sub.T2 value would be in sufficient LD with each other such that
either SNP is useful for the same utilities, such as determining an
individual's risk for psoriasis (or related pathologies such as
Crohn's disease). For example, in various embodiments, the
threshold r.sub.T2 value used to classify SNPs as being in
sufficient LD with an interrogated SNP (such that these LD SNPs can
be used for the same utilities as the interrogated SNP, for
example) can be set at, for example, 0.7, 0.75, 0.8, 0.85, 0.9,
0.95, 0.96, 0.97, 0.98, 0.99, 1, etc. (or any other r.sup.2 value
in-between these values). Threshold r.sub.T2 values may be utilized
with or without considering power or other calculations.
[0614] All publications and patents cited in this specification are
herein incorporated by reference in their entirety. Modifications
and variations of the described compositions, methods and systems
of the invention will be apparent to those skilled in the art
without departing from the scope and spirit of the invention.
Although the invention has been described in connection with
specific preferred embodiments and certain working examples, it
should be understood that the invention as claimed should not be
unduly limited to such specific embodiments. Indeed, various
modifications of the above-described modes for carrying out the
invention that are obvious to those skilled in the field of
molecular biology, genetics and related fields are intended to be
within the scope of the following claims.
TABLE-US-00001 TABLE 1 Gene Number: 1 Gene Symbol IL12B-3593 Gene
Name: interleukin 12B (natural killer cell stimulatory factor 2,
cytotoxic lymphocyte maturation factor 2, p40) Public Transcript
Accession: NM_002187 Public Protein Accession: NP_002178
Chromosome: 5 OMIM NUMBER: 161561 OMIM Information: BCG and
salmonella infection, disseminated, 209950 (1);
{Asthma,/susceptibility to}, 600807 (3) Transcript Sequence (SEQ ID
NO: 1): Protein Sequence (SEQ ID NO: 3): SNP Information Context
(SEQ ID NO: 5):
AAGACACAACGGAATAGACCCAAAAAGATAATTTCTATCTGATTTGCTTTAAAACGTTTT
TTTAGGATCACAATGATATCTTTGCTGTATTTGTATAGTMT
GATGCTAAATGCTCATTGAAACAATCAGCTAATTTATGTATAGATTTTCCAGCTCTCAAGT
TGCCATGGGCCTTCATGCTATTTAAATATTTAAGTAATT Celera SNP ID: hCV2084293
Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP in
Transcript Sequence SEQ ID NO: 1 SNP Position Transcript: 1188 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,93|C,27) SNP Type: UTR3 Context (SEQ ID NO: 6):
CACGGTCATCTGCCGCAAAAATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAG
CTCATCTTGGAGCGAATGGGCATCTGTGCCCTGCAGTTAGR
TTCTGATCCAGGATGAAAATTTGGAGGAAAAGTGGAAGATATTAAGCAAAATGTTTAAA
GACACAACGGAATAGACCCAAAAAGATAATTTCTATCTGAT Celera SNP ID: hCV2084294
Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP in
Transcript Sequence SEQ ID NO: 1 SNP Position Transcript: 1030 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (G,117|A,3) SNP Type: UTR3 Context (SEQ ID NO: 7):
TGTCTGGAAGGCAAAAAGATCTTAAGATTCAAGAGAGAGGACAAGTAGTTATGGCTAAG
GACATGAAATTGTCAGAATGGCAGGTGGCTTCTTAACAGCCM
TGTGAGAAGCAGACAGATGCAAAGAAAATCTGGAATCCCTTTCTCATTAGCATGAATGAA
CCTGATACACAATTATGACCAGAAAATATGGCTCCATGAA Celera SNP ID: hCV7537839
Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP in
Transcript Sequence SEQ ID NO: 1 SNP Position Transcript: 2124 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (C,26|A,94) SNP Type: UTR3 Context (SEQ ID NO: 8):
CCACATTCCTACTTCTCCCTGACATTCTGCGTTCAGGTCCAGGGCAAGAGCAAGAGAGAA
AAGAAAGATAGAGTCTTCACGGACAAGACCTCAGCCACGGK
CATCTGCCGCAAAAATGCCAGCATTAGCGTGCGGGCCCAGGACCGCTACTATAGCTCATC
TTGGAGCGAATGGGCATCTGTGCCCTGCAGTTAGGTTCTG Celera SNP ID: hCV31985602
Public SNP ID: rs3213119 SNP Chromosome Position: 158676366 SNP in
Transcript Sequence SEQ ID NO: 1 SNP Position Transcript: 935 SNP
Source: dbSNP; HapMap; HGBASE; Population (Allele, Count):
Caucasian (G,115|T,1) SNP Type: Missense Mutation Protein Coding:
SEQ ID NO: 3, at position 298,(V,GTC) (F,TTC) Gene Number: 2 Gene
Symbol IL23R-149233 Gene Name: interleukin 23 receptor Public
Transcript Accession: NM_144701 Public Protein Accession: NP_653302
Chromosome: 1 OMIM NUMBER: 607562 OMIM Information: Transcript
Sequence (SEQ ID NO: 2): Protein Sequence (SEQ ID NO: 4): SNP
Information Context (SEQ ID NO: 9):
CTGACAACAGAGGAGACATTGGACTTTTATTGGGAATGATCGTCTTTGCTGTTATGTTGTC
AATTCTTTCTTTGATTGGGATATTTAACAGATCATTCCGR
ACTGGGATTAAAAGAAGGATCTTATTGTTAATACCAAAGTGGCTTTATGAAGATATTCCT
AATATGAAAAACAGCAATGTTGTGAAAATGCTACAGGAAA Celera SNP ID: hCV1272298
Public SNP ID: rs11209026 SNP Chromosome Position: 67478546 SNP in
Transcript Sequence SEQ ID NO: 2 SNP Position Transcript: 1228 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,112|A,8) SNP Type: Missense Mutation Protein Coding: SEQ ID NO:
4, at position 381,(R,CGA) (Q,CAA) Context (SEQ ID NO: 10):
TGCAACAGTCAGAATTCTACTTGGAGCCAAACATTAAGTACGTATTTCAAGTGAGATGTC
AAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACTY
TTTTTTCATAAAACACCTGAAACAGTTCCCCAGGTCACATCAAAAGCATTCCAACATGAC
ACATGGAATTCTGGGCTAACAGTTGCTTCCATCTCTACAG Celera SNP ID: hCV2990018
Public SNP ID: rs7530511 SNP Chromosome Position: 67457975 SNP in
Transcript Sequence SEQ ID NO: 2 SNP Position Transcript: 1015 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,15|C,105) SNP Type: Missense Mutation Protein Coding: SEQ ID NO:
4, at position 310,(L,CTG) (P,CCG) Context (SEQ ID NO: 11):
ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCGG
GAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTM
ATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACATA
CAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID: hCV11283764
Public SNP ID: rs10889677 SNP Chromosome Position: 67497708 SNP in
Transcript Sequence SEQ ID NO: 2 SNP Position Transcript: 2284 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,87|A,33) SNP Type: UTR3 Context (SEQ ID NO: 12):
GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAATA
GGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAK
CAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAAT
TCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID: hCV31222798
Public SNP ID: rs11465827 SNP Chromosome Position: 67497416 SNP in
Transcript Sequence SEQ ID NO: 2 SNP Position Transcript: 1992 SNP
Source: dbSNP Population (Allele, Count): Caucasian (T,117|G,3) SNP
Type: UTR3
TABLE-US-00002 TABLE 2 Gene Number: 1 Gene Symbol: IL12B-3593 Gene
Name: interleukin 12B (natural killer cell stimulatory factor 2,
cytotoxic lymphocyte maturation factor 2, p40) Chromosome: 5 OMIM
NUMBER: 161561 OMIM Information: BCG and salmonella infection,
disseminated, 209950 (1); {Asthma,/susceptibility to}, 600807 (3)
Genomic Sequence (SEQ ID NO: 13): SNP Information Context (SEQ ID
NO: 21):
GGAAAGTTTTCGGAGTTTTACAGCAAGAAAAACACCATTATGTTTGATGACATAGGGAG
AAATTTTCTAATGAACCCACAGAATGGACTAAAGGTAAGACR
TACTTTTACTTGTTATGTGCTCATGTAATCTGGGCTGTGTGGTAGAACTTTTGTAGTAAG
CACTGTTGAATTTCATATATTTTTGGAAGTACTGTATTCT Celera SNP ID: hCV25633374
Public SNP ID: rs12520035 SNP Chromosome Position: 158637948 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 7814 SNP
Source: Applera Population (Allele, Count): Caucasian (A,35|G,5)
African American (A,29|G,3) total (A,64|G,8) SNP Type: INTRON SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,112|G,8) SNP Type: INTRON Context (SEQ ID NO: 22):
TTGGATCTAAATCACAAATATTGGGAAAGGTAAGTTTTAATTGCTTATTTATTTTCTCTT
TACATCAATGAAGAAAAAATTATCATTTTTCATCAGTGACY
CCAGTATATATATAGCTGTCTTAATTTTTATTTAAAATAGGTGACTTCTAAAAACATTTT
CTAATCCAGTGACCTACCCCCAAAAGTATTTTCCCCTTTC Celera SNP ID: hCV7537829
Public SNP ID: rs1433046 SNP Chromosome Position: 158642997 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 12863 SNP
Source: Applera Population (Allele, Count): Caucasian (C,10|T,24)
African American (C,17|T,5) total (C,27|T,29) SNP Type: INTRON;
PSEUDOGENE SNP Source: dbSNP; HapMap; HGBASE Population (Allele,
Count): Caucasian (C,53|T,67) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 23):
CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTG
CACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAAR
CAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTG
ATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693
Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 58289 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,21|A,99) SNP Type: INTRON Context (SEQ ID NO:
24): ATAAGGGACTGTAGCTCGTCATTTGATGTAGTAGGATATGTAATGATTTAGAAATTTTC
ATGACACATTTAAGTGAAAGAAGTATTTTAGAGAACACTGTY
GTAAGCCGTTAGAAAATAGTTCTTAACCTTTGTTTGGTTCAGGATTACCCTTAATTTAAC
AAAGAACCTGTCAACTCTCTGAGGCTGCTCTTGTTTATAA Celera SNP ID: hCV2084259
Public SNP ID: rs7708700 SNP Chromosome Position: 158636313 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 6179 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,26|C,94) SNP Type: INTRON Context (SEQ ID NO: 25):
GCCTAGGCTGGTCTCGAGGTCCTGCACTCAAGCGATCCACCTATCTCGGCCTCTCAAAG
TGCAGGATTACAGGCATGAGCCACTGCGCCCAGCCCAGAAAK
AGTTCTAAAATGGAGAAATATCCTCAAATGCTGTGTTTTGTTATCATGCTTTCATAATGC
ACTTGGTAGAAATCTCAAAGATTTCATGTAGATCTTAAAA Celera SNP ID: hCV2084262
Public SNP ID: rs17665189 SNP Chromosome Position: 158640194 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 10060 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,53|T,67) SNP Type: INTRON Context (SEQ ID NO: 26):
ATCATATTATCTAAAATTAATTTAAAATTATTGAAAGACTATCTTGAGTTGTATAAAGAT
ATTTGAGCAGGTGTCTTTTACAAAACAGCAGAATTCTTTAY
TGAAGCTATAAAATAAGGAAAAGTGCATAAATTTATAGTTCAACAAACTGTAAAGATA
ATTCTTGTAAAAAATTTTATTCCACTAAAATTACTCATGATT Celera SNP ID:
hCV2084263 Public SNP ID: rs10515782 SNP Chromosome Position:
158641855 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 11721 SNP Source: dbSNP; Celera Population (Allele,
Count): Caucasian (C,26|T,94) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 27):
TAAACTCTTTTTCATCATAAAATAGATCAGCCTTAAACATTTGGAAAATATGGCAGTTCT
TTTTATGGAAAACTCTTGCATAATTAAAAATGATTTTAACR
GAGAATTTAATGATAAAGAAAAATGCTTATGATAAAATGTAGGAGGAAACAGGTTATA
TAAATGTATAATGATATCTCAGCTATATAAAAATTTAATAGA Celera SNP ID:
hCV2084265 Public SNP ID: rs7736656 SNP Chromosome Position:
158642268 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 12134 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (A,261G,94) SNP Type: INTRON; PSEUDOGENE
Context (SEQ ID NO: 28):
TGGAATATAATCCCTCTTCTCATACTGTAACTTAATGTCAGGATAAGATAAAACACATG
TAAAAATTTCATAAATAGTATTAAAAATTACCAGTAACTTGW
GTGTAGCAGAGAAATTAGAAAAGTTTATCCTACTAAAAAAACAATTACTCATAATTTTC
CTTTTTAAAGATAACCACTGTTACCATCTTGGTATATAGTC Celera SNP ID: hCV2084266
Public SNP ID: rs10042630 SNP Chromosome Position: 158643346 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 13212 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(A,26|T,94) SNP Type: INTRON Context (SEQ ID NO: 29):
CAAAGGCCCCCTTCCATTTCTCCTCTCCAGAGTGTTCCAGTAAGAACATCCCCTTCTAGC
TATTTCACACATGGACAACCAAGAAATAGTCATTTACAGAR
CATTTTGCATTTGTACAATTTCACTCGTTATTTCTCCCCCAGTACCTAATGGGGGCTGCA
GCGTGTACTCTGTTCGTGGTTAAATTCTGCTGCCAGAAGT Celera SNP ID: hCV2084270
Public SNP ID: rs2082412 SNP Chromosome Position: 158650367 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 20233 SNP
Source: dbSNP; Celera; HGBASE Population (Allele, Count): Caucasian
(G,93|A,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 30):
AGGGGCTACAGGCCCCATGCAATTCTAAAATCCAGCAGAGCAGTCAAATCTTAAAGCT
CCAGAATGATCTCCTTCAACTCCATGTCTCACATTCAGGTCAY
GCTGAAGTAGGTGCCCGAGGTCTTGGGCAGCTCTGCCCCTGTGACTTTGCAAGGTACAG
CCTCTCTCCCGGCTGCCTTCACAATCTGGCATTGAGTGTCT Celera SNP ID: hCV2084272
Public SNP ID: rs2116821 SNP Chromosome Position: 158657658 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 27524
SNP Source: dbSNP; Celera; HapMap; HGBASE Population (Allele,
Count): Caucasian (T,47|C,67) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 31):
ATAAAAACTAAAGATAACATCTTGACATATGTCCCTGAGTTATTTTTCAGAAACGCAGA
CTCCCACCAGATGGAAAATGTTACATAGGCTGTCACACAGAY
TGAACTCTGACTGCCATTCCTTGTTCTAATTTTCTTCCTGAGGGGCCTGAAGAAAGTCAT
GCACACAGTCCAAACCTGAACATTCCTTTCTGTGGACCCC Celera SNP ID: hCV2084274
Public SNP ID: rs1433047 SNP Chromosome Position: 158660134 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 30000 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,26|C,94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 32): GAACAGATGACCAGGGGTGACTCAGGACAGAGCAGGTGACCAGGGGAACAGATGTGA
ACTGCTGATTAGAACTGGTGGAAAAAGTTGTTTACTGAAACTAY
GGGCGAGGAGAATGAGGAAGTTAAACTTTAAAATGGAGAACAAAGAACTGAACATACT
GACATACTGATTCTTTGAAGAGAAATTTAGAACTCACTGTAT Celera SNP ID:
hCV2084277 Public SNP ID: rs6874870 SNP Chromosome Position:
158662099 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 31965 SNP Source: dbSNP; Celera Population (Allele,
Count): Caucasian (T,23|C,93) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 33):
CCACTTCCAACATTGGGGATCAAATTTCAACATGAGATTTGGAGGGACAAATATGCAAA
CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTY
TGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTG
TATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTG Celera SNP ID: hCV2084281
Public SNP ID: rs7730390 SNP Chromosome Position: 158663370 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33236 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,91|C,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 34):
GTGATAATGTCTGGGCTTGGCAATTACCTTCAGTCTGTTCTCCTCCTGTGATACAGTTAA
TTTTTCCTAATTAATGAGATTCCTGGGGAGGAAACTCATGR
CAATTGAGTGCCTTTTTGGAAGATCTATCTTTAGGCAGACGAGGCAAGTTCAGAGACCA
CCCTTCCCTGTGCTTTTGAAACAGGGGTGAGAGACAGCAGG Celera SNP ID: hCV2084283
Public SNP ID: rs1549922 SNP Chromosome Position: 158664126 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33992 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,63|A,53) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 35):
ACCAAGGCCAGGTAAAAACCACCCCTTCATCCCCTAAACCTTGCAAGAAGCACAGGGT
CCAGAATTATGCTTCTTTCAGGTTCTAAATAGCACAATAAAAY
TAATAACAATAAGCTTTTAGTTATTAGATCAGGTACATTTTACTTTACAGTAAGCTTTTA
CTTATTGGATCAGGTACATTTTAAAGCAATTTTTGAACAT Celera SNP ID: hCV2084288
Public SNP ID: rs6870828 SNP Chromosome Position: 158671090 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 40956 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,54|T,64) SNP Type: INTRON Context (SEQ ID NO: 36):
AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCT
ATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCK
AACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAAT
CAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293
Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45394 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,93|G,27) SNP Type: UTR3; INTRON Context (SEQ ID NO:
37): ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATA
TCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAY
CTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTT
ATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294
Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45552 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (C,117|T,3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 38):
GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAAT
GCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTY
AAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACA
GATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295
Public SNP ID: rs2195940 SNP Chromosome Position: 158676930 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 46796 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (C,110|T,10) SNP Type: INTRON Context (SEQ ID NO: 39):
GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGG
CCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGY
GAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAA
ATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296
Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 47104 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (T,26|C,94) SNP Type: INTRON Context (SEQ ID NO:
40): CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCA
GAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACM
TTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGT
CTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297
Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 50008 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,110|C,10) SNP Type: INTRON Context (SEQ ID NO: 41):
GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAA
GGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCK
TTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAG
TGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298
Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 51532 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,65|T,55) SNP Type: INTRON Context (SEQ ID NO: 42):
TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACT
TAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATY
GTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCC
ATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC Celera SNP ID: hCV2084301
Public SNP ID: rs3213093 SNP Chromosome Position: 158683557 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 53423 SNP
Source: dbSNP; Celera; HGBASE Population (Allele, Count): Caucasian
(C,93|T,27) SNP Type: INTRON Context (SEQ ID NO: 43):
TCCCATGATGGTCAAGGAATAATTTTGGAGGAGACGTTTAACTTTAAAAAAAAAAATAC
AATCATTAGTTTCATGTTTGTTTAAAAGAAACTTTGTTTTCS
TAACCAACATTTGAGCTCCATTCATCTCTTGATGCAGGGAGAGATGTTATTGTAAATGTC
TAGTTCTTTATGTTACTTTACAGTAGGGTTTTTAAAAGAC Celera SNP ID: hCV7537756
Public SNP ID: rs1368437 SNP Chromosome Position: 158639557 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 9423 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (C,112|G,8) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 44):
TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAA
AGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACAK
GGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGT
CCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839
Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 44458 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (G,26|T,94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 45):
GGACAGTAGAGGTGCTTTCCTGTGGGATCCCCAATCTCTCCCCGCCTTCAGGTGAGTCC
TGCTGATGCTCAGGCTGCCCTTGGAACAGGGACCTTGGCCAY
AGTTTCCTTATCTGTAATAATGGGATGAGAATTCCTCCTGCACAGGGTTGTTAGGGACCT
CGTGAGGCAGCTTCTATGGCTGCCTTTGGTGCTTAGTTTT Celera SNP ID: hCV11316602
Public SNP ID: rs1865014 SNP Chromosome Position: 158671666 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 41532 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,20|C,94) SNP Type: INTRON Context (SEQ ID NO: 46):
TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGC
ACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGAR
ATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACAT
GTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290
Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 48751 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,93|A,27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE;
INTRON Context (SEQ ID NO: 47):
GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCA
GTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGR
CTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACT
TGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID:
hCV15894459 Public SNP ID: rs2546892 SNP Chromosome Position:
158688053 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 57919 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,103|A,17) SNP Type: INTRON Context
(SEQ ID NO: 48):
GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGC
AGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAY
GAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTT
CATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID:
hCV29927086 Public SNP ID: rs3213094 SNP Chromosome Position:
158683347 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 53213 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,93|T,27) SNP Type: TRANSCRIPTION
FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 49):
CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTC
CTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAM
CGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGT
GAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID:
hCV31985602 Public SNP ID: rs3213119 SNP Chromosome Position:
158676366 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 46232 SNP Source: dbSNP; HapMap; HGBASE; Population
(Allele, Count): Caucasian (C,115|A,1) SNP Type: MISSENSE MUTATION;
INTRON Context (SEQ ID NO: 50):
CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTG
TCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTR
TGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATAC
TCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID:
hCV27106395 Public SNP ID: rs11574790 SNP Chromosome Position:
158676424 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 46290 SNP Source: dbSNP; Celera; HapMap; Population
(Allele, Count): Caucasian (G,110|A,10) SNP Type: INTRON Context
(SEQ ID NO: 51):
TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATG
AAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCR
TATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAA
TGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID:
hCV27467944 Public SNP ID: rs3181224 SNP Chromosome Position:
158673428 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 43294 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (A,110|G,10) SNP Type: INTRON Context
(SEQ ID NO: 52):
GTAGTGGCTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAA
AACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGR
TCATGTCGCAAAAGCACTGGGCATGGTGGGAGCCAGAACATCTCACCTCTGCCCCAGGC
TGGCCAGAAATTTGGGGAAAGGTCCCAGTTCTCAGTGCTTA Celera SNP ID:
hCV27467945 Public SNP ID: rs3181225 SNP Chromosome Position:
158673201 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 43067 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,102|A,18) SNP Type: INTRON Context
(SEQ ID NO: 53):
GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGAC
GGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAAS
TCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAG
GCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935
Public SNP ID: rs3212217 SNP Chromosome Position: 158687708
SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 57574
SNP Source: dbSNP; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,93|C,27) SNP Type: INTRON Context (SEQ ID NO: 54):
TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACA
GAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCM
TTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATA
GAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507
Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 56905 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(C,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 55):
GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTG
TCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTM
CCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAA
AGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID:
hCV27508808 Public SNP ID: rs3212218 SNP Chromosome Position:
158687174 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 57040 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,81|A,25) SNP Type: INTRON Context
(SEQ ID NO: 56):
AATGAACAGAAAATGGAAGTGAGGTACAGAGACAGCTTGGTTGGTTACAGCTAGGTGT
TTGCTTTATTTGAGCATGGTCTGATCAGTTGGTAACCTATAAY
TGATTGGAGGTTTGCTGCTGTGTTTTACTGCTGAGGCTCAGCTATTAGCTACAAAAATAT
ATTAAATTAGCTTTCAGTCAGTTCATACCAAGTTAGGTTG Celera SNP ID: hCV28001193
Public SNP ID: rs4921466 SNP Chromosome Position: 158665350 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 35216 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(T,112|C,8) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 57):
CTGTATGCCCAGCAAAGGGCTGGTGGCTGGAAGGACATAGCTTTCTGAGTTAGGACTGG
AAGGCTTCTGTACATGTCCAAAGTCAACCTTCATATTCATGR
GGAGGGAAAAAGAAGTGGGCTTTAGGATTGCCTCTCCTTGTTGGCCTGCTCTGAGAAAA
ACAATCGCGGGAGGGTGAGGCGGGAGAATCGCTTGAGCCCA Celera SNP ID:
hCV29349409 Public SNP ID: rs6859018 SNP Chromosome Position:
158669570 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 39436 SNP Source: dbSNP Population (Allele, Count):
Caucasian (G,91|A,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 58):
CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCA
ACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGM
ACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAG
GAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID:
hCV30449508 Public SNP ID: rs3212220 SNP Chromosome Position:
158686773 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 56639 SNP Source: dbSNP; HapMap; ABI_Val; HGBASE
Population (Allele, Count): Caucasian (C,93|A,27) SNP Type: INTRON
Context (SEQ ID NO: 59):
GGATTACACAAATGTGTGAACAGCAGAAGGTAGAAACATTGAGGGTTATGGTACAGTC
TGTTTGCCACAATCCCTGAATCCATTCTTTAAAAAGTTGGTAK
AAAAATACCTACTTTAGAGGGTTGTTATGTGAATTCAAAACAAGATAACATATATCGAG
TGTTTACGTGGTACCTGGCACATAGTGAGCATTCAATAAAT Celera SNP ID:
hCV30557642 Public SNP ID: rs10056599 SNP Chromosome Position:
158655488 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 25354 SNP Source: dbSNP; HapMap; ABI_Val Population
(Allele, Count): Caucasian (T,93|G,27) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 60):
TACTACAGGGGAGAACACTGGTGGACAGACACAACCTAAACAAAGTGATCAAAGTTAA
TTTCACCAGTACTGAGAGACATTGATTTCATGCCCCTCCTGAY
GAGATTCACTGAGAAGGGCACAGTATTACTGCTGTAGGATGCTTGACAAAAATGTAGA
ACCCAAATTTAATCATGAAGAAACATGAGACAAATGTCACTT Celera SNP ID:
hCV29619986 Public SNP ID: rs10072923 SNP Chromosome Position:
158668354 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 38220 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (T,93|C,27) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 61):
CCGATAGTGCCCACGGTGAACCCGTATTATTGTTCCTCTATCAGGTAGCTCAATATATAT
GAAAAGATAGTGGAATCTGCTAGGTGATACAGGTGAGGGAR
GATCCTTTGATTTGAGTTGATGACAGGAATTCAGCTGAGTCATGTTTTAGGATGCAGGC
TCATACCTAGAACCATCTTGAAAGTACCATCTGGGAGCAAG Celera SNP ID:
hCV31985608 Public SNP ID: rs12652431 SNP Chromosome Position:
158654672 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 24538 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (A,94|G,10) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 62):
GACTTTTCAGGAATCTAGAGGTAAATCAATTATTTAATTGAATACAAATCCCTCTTACTT
TTATTCCCAGTTCTTAATTCTCTGGAGCACTGATTGCTATY
ACTTCTTGTTGGATAATCTGTGAGGAGAACTGCTGTAGCTTCCTAAATAAGGCTTTTGAA
AGAGCCAGTGGTTTGTCAGAAAAACATGTGACTAAAATCC Celera SNP ID: hCV30629526
Public SNP ID: rs4921458 SNP Chromosome Position: 158648241 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 18107 SNP
Source: dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (T,26|C,94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 63):
ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCC
AGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCR
TCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTT
TAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748
Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 59412 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,94|G,26) SNP Type: INTRON Context (SEQ ID NO: 64):
ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGA
GAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCY
GAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCC
TGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592
Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 66621 SNP
Source: dbSNP; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,76|C,44) SNP Type: INTRON
Context (SEQ ID NO: 65):
AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGT
ACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTW
TGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGA
CCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID:
hDV75439995 Public SNP ID: rs3213097 SNP Chromosome Position:
158681257 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 51123 SNP Source: CDX; dbSNP Population (Allele, Count):
Caucasian (T,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 66):
GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATG
TGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGAG/TTAGA
CCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATG
CCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID:
hDV79877074 Public SNP ID: rs17860508 SNP Chromosome Position:
158692783 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 62649 SNP Source: dbSNP Population (Allele, Count): no_pop
(G,-I,-) SNP Type: INTRONIC INDEL Context (SEQ ID NO: 67):
GTTTACAATGAGGATATTTTAGGGAAAGAATACTAATCTAGGTAGTGAATTGCCATAAG
TATAAAAACTGTTGACTTGGAAGAAAAGTGGTTATGTTGTCY
TTAATGGTTTCTGTTTAAGGCTTGGAGAGAAGTGCTTTTCTTAATATGTACTGCACCAGG
TAAAGGTACAAAAATGTATTCTTGAGTCTTGAGAAGAAAT Celera SNP ID: hCV2084260
Public SNP ID: rs13153734 SNP Chromosome Position: 158639291 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 9157 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
Celera Population (Allele, Count): Caucasian (C,98|T,20) SNP Type:
INTRON; PSEUDOGENE Context (SEQ ID NO: 68):
CGAAATCAGTTATTGGACTAATGATACCTATAGCAGCTCTTCAGTGTAAAAGGTAAGGA
ATGGAAAAACAGGTTGTTACAGTAAGCAACTGAAACTTATTY
TTTATTCATGGAAAGTAAAATAGTTCCTTGAGAGGAAGAGGAACTACAGGATAGGGAC
TGGGAAAAAAGGATATGCAAAAAAACGCAGATTAGTTGCATT Celera SNP ID:
hCV2084269 Public SNP ID: rs6895626 SNP Chromosome Position:
158646681 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 16547 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (T,26|C,94) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 69):
CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTTTGGGGTATTGAAAATATT
CCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTS
TATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTGTAGAGTATGTGAACTATA
CCTCATTACAGCTGTTAGAAAAATGTATACCTTGGTGGTCA Celera SNP ID: hCV2084282
Public SNP ID: rs2099327 SNP Chromosome Position: 158663429 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 33295 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
Celera; HGBASE Population (Allele, Count): Caucasian (G,100|C,20)
SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 70):
AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGC
CCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCK
CCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAA
CCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051
Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 45847 Related
Interrogated SNP: hCV15894459 (Power = .51) Related Interrogated
SNP: hCV27467945 (Powe = .51) SNP Source: dbSNP; HapMap; HGBASE
Population (Allele, Count): Caucasian (T,102|G,18) SNP Type:
TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 71):
TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACC
ATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACY
CTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCC
TTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID:
hCV15879826 Public SNP ID: rs2288831 SNP Chromosome Position:
158682591 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 52457 Related Interrogated SNP: hCV2084270 (Power = .51)
Related Interrogated SNP: hCV2084293 (Power = .51) Related
Interrogated SNP: hDV71045748 (Power = .51) SNP Source: dbSNP;
HapMap; ABI_Val; HGBASE Population (Allele, Count): Caucasian
(T,91|C,25) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON
Context (SEQ ID NO: 72):
TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAAC
GATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAY
AGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTG
GCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033
Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP in
Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 53693 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
HapMap; HGBASE Population (Allele, Count): Caucasian (C,102|T,18)
SNP Type: INTRON Context (SEQ ID NO: 73):
TCACAAGTCTGTTATGTAACCATAGTTGGGACTGGAGTCTGCTCCTCTGATTCCCAGTCC
TAAGATCTTTGGCTTAGACATTTAGTACATTTTGTAGTGGS
TAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGC
ATTGCATGCACTGAAATTAATCGAATGCTAAGAGGTCATGTC Celera SNP ID:
hCV27467946 Public SNP ID: rs3181226 SNP Chromosome Position:
158673108 SNP in Genomic Sequence: SEQ ID NO: 13 SNP Position
Genomic: 42974 Related Interrogated SNP: hCV15894459 (Power = .51)
Related Interrogated SNP: hCV27467945 (Power = .51) SNP Source:
dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (G,102|C,18) SNP Type: INTRON Context (SEQ ID NO: 74):
TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGA
AAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAW
GGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATG
GGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID:
hCV32389155 Public SNP ID: SNP Chromosome Position: 158681347 SNP
in Genomic Sequence: SEQ ID NO: 13 SNP Position Genomic: 51213 SNP
Source: HGBASE; dbSNP Population (Allele, Count): no_pop (A,-IT,-)
SNP Type: INTRON Context (SEQ ID NO: 75):
TCTGGCGAATTCTACGTGAAATGTCAGGAACCAGTGAAGGGTGTTAAGCATAGAATGA
CAATCTAATTTTTTTTAACAGCCTTATTGAGATAGAATTTACM
TATCACAAATTTACCCATTTGAAGTGTGCAGTTCAATGGTTTTTAGTGTATTTAGAGAGC
TGTACAACCATCACTGTAAGCTAATTTTAGAACCTGATTT Celera SNP ID: hCV31985611
Public SNP ID: rs13161132
SNP Chromosome Position: 158649646 SNP in Genomic Sequence: SEQ ID
NO: 13 SNP Position Genomic: 19512 Related Interrogated SNP:
hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap Population
(Allele, Count): Caucasian (A,88|C,16) SNP Type: INTERGENIC;
UNKNOWN Gene Number: 2 Gene Symbol: IL23R-149233 Gene Name:
interleukin 23 receptor Chromosome: 1 OMIM NUMBER: 607562 OMIM
Information: Genomic Sequence (SEQ ID NO: 14): SNP Information
Context (SEQ ID NO: 76):
TCTGGCAAAGAGAAGGCCACACACCAGGAAGCCCCTGAGGGTACAGGGACATTACTGA
TTATAAAGGAGGGAAGGAACAAGCTATGTGTGTTCCTGATAAM
CCCTGGCCCTCGGGATTGGCTGTCAAGGGGCTCAAAACCCAGTCCAAGGGACAAACAC
ATCATCCAAGCCTTGCAATGCAGTGATGTAAGTGCAATGATA Celera SNP ID: hCV261080
Public SNP ID: rs10889675 SNP Chromosome Position: 67494804 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 100047 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (C,105|A,15) SNP Type: INTRON Context (SEQ ID NO: 77):
TTAGACAACAGAGGAGACATTGGACTTTTATTGGGAATGATCGTCTTTGCTGTTATGTTG
TCAATTCTTTCTTTGATTGGGATATTTAACAGATCATTCCR
AACTGGGTAGGTTTTTGCAGAATTTCTGTTTTCTGATTTAGACTACATGTATATGTATCA
CCAAAATTTAGTCATTTCAGTTGTTTACTAGAAAAATCTG Celera SNP ID: hCV1272298
Public SNP ID: rs11209026 SNP Chromosome Position: 67478546 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 83789 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,112|A,8) SNP Type: MISSENSE MUTATION; ESE; INTRON Context (SEQ
ID NO: 78):
AACTCCTGGACTCAAGAACTCTGCCCACCTTGGCCTCCCAAAGTGCTGGGCTTACAGGC
AGGAGCCACCATGCCTGGCCTATGATTATGCTTTTTCTTGAR
GTCATCATCTTCTATATTAGTTTCCTATTACTACTGTCACAAATCATCACAAACTTGAAA
GCTTAAAACAACATGAATTTATTATCTTATAGTTCTGGAG Celera SNP ID: hCV1272302
Public SNP ID: rs2201841 SNP Chromosome Position: 67466790 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 72033 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,87|G,33) SNP Type: INTRON Context (SEQ ID NO: 79):
GACTAGAAATTGAGGCTATACCTGCAATGGGAGCAATGTACCTGCCTTTGTCCCAACTC
AGGGGAAAAATTCAAGCTGCTTTATCACAATGCAAACTTCGY
GGGGGAGAAAGGGTTTCTTTCTATAATTCTTGTATTCAAGAAGGATTCATTGAACTACT
GAATGTCCTTACTGTTATATGTGCAAGGCCATTTGAAGGAT Celera SNP ID: hCV2720250
Public SNP ID: rs4655531 SNP Chromosome Position: 67500366 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 105609 SNP
Source: Celera; HGBASE; dbSNP Population (Allele, Count): no_pop
(C,-IT,-) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 80):
AATTGAACCCAGGCCACCACTGTGAAAGTAAAAAACTTTAGCTACTGAGCTACAGTACT
GGGTAGTCTCCATTGTGCTTCCCAGAAGGGCTCTAAAGTACK
TAATTTTGAGCTTGCAAAAGCTTTTAACTACTCAACTTAATTTTTAGAGCTAACTGTGAC
ATGAACCCTAAAATTCCTGTTCCCTTGAAGGCAGAGACCA Celera SNP ID: hCV2720255
Public SNP ID: rs10889674 SNP Chromosome Position: 67490116 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 95359 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(G,43|T,77) SNP Type: INTRON Context (SEQ ID NO: 81):
TATTATTATCTCTATTTTCCAAAAGAGAAAACCTGAGACTCAGCAAGTTCATAATTATGC
CCCAAGGTCACAGAGCTGATAAGAGGCAGAGTTTAATTCAM
ACCCAGGTATATCAGGCCACGCTCTTGGTCATTCTGCTCTACTGCTTAGACCCCTTTGCC
GAGCACTGTGTTGACCTGAGGGCTGTCTATCCTCTTCCAG Celera SNP ID: hCV2989999
Public SNP ID: rs1343152 SNP Chromosome Position: 67476920 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 82163 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,74|C,42) SNP Type: INTRON Context (SEQ ID NO: 82):
GTGCAACAGTCAGAATTCTACTTGGAGCCAAACATTAAGTACGTATTTCAAGTGAGATG
TCAAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACY
GTTTTTTCATAAAACACCTGAAACAGGTGAGTGTACTTATATATTTTATTCTGTTGGGCT
TTTCTTTATATATCTTTTCTGCTGAGCACAGTGGCTCACA Celera SNP ID: hCV2990018
Public SNP ID: rs7530511 SNP Chromosome Position: 67457975 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63218 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,15|C,105) SNP Type: MISSENSE MUTATION; ESS; UTR5 Context (SEQ ID
NO: 83):
GTGCAATCTCGGCTCACTGCAACCTCCATCTCCTGGGTTCAAGTGATTCTCATGCCTCAG
CCTCCCAAGTAGCTAGGAATACAGGCACACACCACCATTTS
CAACTAATTTTTATATTTTTGGTGGAGACGGGATTTCACCATGTTGGCCAGGCTGCTCTT
GAGCTCTTGGCCTCAAGTGATCTGCCTGTCTTTGCCTCCC Celera SNP ID: hCV8367042
Public SNP ID: rs1008193 SNP Chromosome Position: 67492499 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 97742 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,82|C,38) SNP Type: INTRON Context (SEQ ID NO: 84):
TTGAGTATTTCTAAGCTGCTCGATAGATTAGAGTTGTTTGGTGTGGCAGTTCCCCAGTGT
GTCCAGTTGCTCACAAATTTTGACTTGAATGTTCTTTGCCR
AATTGGCACTGAGTTTCTCCTTCTTGCCATCATTTGCTTCATGAAATAATCTTTCTTTCGT
TTACATTTATAATCAAGTGCAGTAGAAAGATTTTAAATG Celera SNP ID: hCV8367043
Public SNP ID: rs1343151 SNP Chromosome Position: 67491717 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 96960 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,73|A,47) SNP Type: TRANSCRIPTION FACTOR
BINDING SITE; INTRON Context (SEQ ID NO: 85):
GCAAGACCCTGTCTCAGGAAAAAAAAAAAAAAGAGGAAAAAGAAGAAAAAGAAAAAG
AAACATGAAGAAAGGTAAGGGCACTCTGAATTATCAATCAATTR
CAAGCCAAGTGCTTAGGTTCAGTACAGTTCCCTAATTATAGATGCCTACACAGACCTAC
CTACACCTTGATATTTCTGTGGGATCAGTGGAGGTTAGGAA Celera SNP ID:
hCV11283754 Public SNP ID: rs10489628 SNP Chromosome Position:
67476695 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 81938 SNP Source: dbSNP; Celera; HapMap; ABI_Val
Population (Allele, Count): Caucasian (G,66|A,54) SNP Type: INTRON
Context (SEQ ID NO: 86):
ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCG
GGAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTM
ATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACAT
ACAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID:
hCV11283764 Public SNP ID: rs10889677 SNP Chromosome Position:
67497708 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 102951 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (C,87|A,33) SNP Type: UTR3 Context (SEQ
ID NO: 87):
AAAATCCATTGCTGTAGAGGTCAGACACACTCTTTAAGAGAAGGAAGTGTCATCATAAA
AGACAACATAGGGAATGGACAGAAAATGTGGACAGAAAGGCR
GAGTGGATATGATTGCCCAAGCCATTGAAACGGGAGAGTTCCCTGACTCCTGTCGCATA
TCATGTGGCTCATCTATTCTGCCAAGGCACATGCTCAAACC Celera SNP ID:
hCV27952715 Public SNP ID: rs4655692 SNP Chromosome Position:
67464253 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 69496 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (A,25|G,93) SNP Type: INTRON Context
(SEQ ID NO: 88):
CAGCCTAAATTTTAGGGCTTTATTATATAACATTCTCTTTTTAAATATGCGGTAGTTACG
GTCACCTTGGAAAGTTCTACAAAATATCCCTTAAGTTTTTY
GAACTTTCCCACATGGGAATCTTCTGGTTATGAGAGTTTGCTCTATTTAATATGTGTACG
GTTTCACTGCTAGGGTGGTTCTCCCACTTATCTTGAATCT Celera SNP ID: hCV30243123
Public SNP ID: rs6693831 SNP Chromosome Position: 67493455 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 98698 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,30|C,90) SNP Type: INTRON Context (SEQ ID NO: 89):
ACTCTATAACTGCCTAGCAAGATTATGCAAATTGATAACTACCATTTATCATTTACGAA
GTACTCCTGTGTATAAGCTTGTTTGATTATGATGTCAGCCAY
ATTTGGTAGTGTAATTAGCGCTACTTTACAAAAGCGGAAACTGGGCATGACTTACTAAA
TAGTACATTGCTGGTGGGTAATGACACCTAAACTATAACAA Celera SNP ID:
hCV30279129 Public SNP ID: rs10489629 SNP Chromosome Position:
67460937 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 66180 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (T,58|C,62) SNP Type: INTRON Context (SEQ ID NO:
90): AATCAGTATGATTGTAACCAGCTTTAGACATTGTTACAGCAATTGGGAATTCTCACCTGT
GTCAGACAAGCCAAATGAAGCTCACCACTAAGAATTTATAY
GAAATTTGCATGCACAAGCCGACCACATTTGCCAGAGATGCACTTCTAAAAACCCACTG
ACATCAGATACATGTAGCCCAACTTTCTCAAACAAAAAGTT Celera SNP ID:
hCV31222826 Public SNP ID: rs10789229 SNP Chromosome Position:
67478162 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 83405 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (C,50|T,62) SNP Type: TRANSCRIPTION FACTOR
BINDING SITE; INTRON Context (SEQ ID NO: 91):
ACCCACTGACATCAGATACATGTAGCCCAACTTTCTCAAACAAAAAGTTGTTTCCTGGG
GTAGTTGTGCACTCTGGAAAAACAGTCACTCTGTGGCCTAAR
GTAAAGGTTAATTTTGCTTCCCCCCACCCTTTCTCCTTTGAGACCTTTGCTTTGAGCAGA
GTAAAGAGAATAGTAATTCTGGTATCAAATGAAGACTAAT Celera SNP ID: hCV31222825
Public SNP ID: rs10889671 SNP Chromosome Position: 67478314 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 83557 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,14|G,106) SNP Type: INTRON Context (SEQ ID NO: 92):
GGTTGAAGTATGGTCCACTGGGATTGGCCAAGACTCAGTTACTGTTACAGGCACATACT
CCTAAGTCAGGTTTTCACTCTTGTCTGCCTGTTAAGTTAGGW
TACAGTTCATCCACAGGGATTCAAATATAGAGGTATGAAGTCCTTCTCAGGCCATATTT
AGTTTGCTTTAACACTTGAATTCCACCCAAACAAATCAGCT Celera SNP ID:
hCV31222811 Public SNP ID: rs12085634 SNP Chromosome Position:
67491301 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 96544 SNP Source: dbSNP Population (Allele, Count): no_pop
(A,-IT,-) SNP Type: INTRON Context (SEQ ID NO: 93):
ATGACACATGGAATTCTGGGCTAACAGTTGCTTCCATCTCTACAGGGCACCTTACTTCTG
GTAAGAAAATACAACTTAGGCTTTTTGAGTAGTCTTTTAGK
AATTGCCCATTTTAACCCATCATACTGAAAAAATCACATCAGGTGTTAAGTTTCTGGAC
AATAAGATATGCCTTATGTCTTCCATAGGAAAATAATAGAC Celera SNP ID:
hCV31222838 Public SNP ID: rs11465804 SNP Chromosome Position:
67475114 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 80357 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (T,111|G,9) SNP Type: TRANSCRIPTION FACTOR
BINDING SITE; INTRON Context (SEQ ID NO: 94):
GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAAT
AGGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAK
CAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAA
TTCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID:
hCV31222798 Public SNP ID: rs11465827 SNP Chromosome Position:
67497416 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 102659 SNP Source: dbSNP Population (Allele, Count):
Caucasian (T,117|G,3) SNP Type: MICRORNA; UTR3 Context (SEQ ID NO:
95): TAGAAGTGGCTCTGTTTCAAGCTCTGGTAAGCCTATTAGCTAACTCTTTCCCCAACCTCA
TGTCATCTGAACAAAGGGTTTCTAGGCTAAAAATAAAATAM
TTTTTAAAAGTTCAAAAACAACTGGTCAACAGAATAGAGTCTGAGTTCTGTAACACAAG
ACTTCTGTGATCTGATCCACTCACCATTCCAGCTTTACTCC Celera SNP ID: hCV261079
Public SNP ID: rs10889676 SNP Chromosome Position: 67495155 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 100398
Related Interrogated SNP: hCV11283764 (Power = .51) Related
Interrogated SNP: hCV1272302 (Power = .51) SNP Source: Celera;
dbSNP Population (Allele, Count): no_pop (A,-IC,-) SNP Type: INTRON
Context (SEQ ID NO: 96):
ACATTTTTTTTCAATTTCATGGAAAAGAGGTTTTTCATTTTTCCAAAAATTGTACCAAGG
TAAAGCAAAGTTCTAGTTGATGCAGGTGCATTGTATAGGCR
TTAGCAATACTGCCCTCATTATGCACTCATTAGACAGTAGTGCAACCCCAAGAAAAGGA
TGGTTAGATATTTCTTTATAGCAATGCAAGAACAGCCTAAC Celera SNP ID: hCV2720226
Public SNP ID: rs2863209 SNP Chromosome Position: 67505934 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 111177
Related Interrogated SNP: hCV31222786 (Power = .51) SNP Source:
dbSNP; Celera; HGBASE Population (Allele, Count): Caucasian
(G,12|A,106) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 97):
ATTGAAAAGAAGCAGAGCAATAGAGATGAGAGGAAAATCTGAAAAGATAATGACACA
ATTTCCCACTTAATTTTCATTAAGTAAGAGATGAAAACTTTAGM
CTCGGCATCAGGAAGTTTGATTTCTTTAATTAATTTTTTTTTTGAGTCAGGGTCTCACTCT
GTTGCCCAGAGTGAGTGCAGTGGCATGGTCACAGCTCAC Celera SNP ID: hCV2720251
Public SNP ID: rs11465817 SNP Chromosome Position: 67493685 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 98928 Related
Interrogated SNP: hCV11283764 (Power = .51) SNP Source: dbSNP;
Celera; HapMap Population (Allele, Count): Caucasian (C,66|A,42)
SNP Type: INTRON Context (SEQ ID NO: 98):
CCTTGAAGTCACTTCTGTCAGCTTTTAATTATCAGGAAGGAGGAGACTGGCAAGGCTGC
ACCAGGACCCCTTTGAGTTCAGACTGAAAGTTAGGTACCAGK
GTTGCTCACCCCACCCTGGTCAGAATCATTCATTAGCAGTTTCCTGACAGCCTTTATAAC
TAGACCAGGCTGCCAGGAAAAGAAAAGAGCAGAGAGAAGT Celera SNP ID: hCV2990001
Public SNP ID: rs12030948 SNP Chromosome Position: 67474353 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 79596 Related
Interrogated SNP: hCV2989999 (Power = .51) SNP Source: dbSNP;
Celera; HapMap Population (Allele, Count): Caucasian (G,78|T,42)
SNP Type: INTRON Context (SEQ ID NO: 99):
CTAAATAAATAAATAAATAAAGTAAAATAAAGATAAAAGTCTTAAGCTTCAGGTAGAA
GGAAATAGGAACACCACAGTTTAAATTTAAGGTCTGTTTCCTR
AGGAGAAAAATCACTTAAGAGACAAAAATACCAATTAAAATTAAGTATCCCTGAAAAC
TTGGATTTATTAAAGTTTAACATGTTAGCTAAGAGAAACCAT Celera SNP ID:
hCV2990015 Public SNP ID: rs7528924 SNP Chromosome Position:
67461624 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 66867 Related Interrogated SNP: hCV27952715 (Power = .51)
SNP Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele,
Count): Caucasian (G,25|A,95) SNP Type: INTRON Context (SEQ ID NO:
100): CAGCACTTTGAGAGGCCAAGGCAGGAAGATTGCTTGAGCCTAGGAGTTTGAGACTGGC
CTGGGCAACATAGTGAGACCCTAGTCTGTACAGAAAAATAATM
ATTATTATTAGCCTGGGTGGTAGAATGCATTTGTAGTCGCAGCTACTTGGGAAGCTGAG
GTAGTAGGATTGCGTGAGCCCGGGAGTTTGATGCTGCAGTG Celera SNP ID: hCV2990016
Public SNP ID: rs11465802 SNP Chromosome Position: 67458186 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63429 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(A,89|C,31) SNP Type: INTRON Context (SEQ ID NO: 101):
ATGTCAAGAAACAGGCAAAAGGTACTGGCAGCCTTGGAGTTCACTGTTTTTTCATAAAA
CACCTGAAACAGGTGAGTGTACTTATATATTTTATTCTGTTR
GGCTTTTCTTTATATATCTTTTCTGCTGAGCACAGTGGCTCACACCTATAATTCCAGCAC
TTTGAGAGGCCAAGGCAGGAAGATTGCTTGAGCCTAGGAG Celera SNP ID: hCV2990017
Public SNP ID: rs7518660 SNP Chromosome Position: 67458031 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 63274 Related
Interrogated SNP: hCV30279129 (Power = .51) SNP Source: dbSNP;
Celera Population (Allele, Count): Caucasian (G,55|A,59) SNP Type:
INTRON Context (SEQ ID NO: 102):
GTAATCTATCACACATGAAAAAAGCTTTTATCAAGCTTAAAGGATTACAGCATTGTTTG
ATCTTCTGCAAATGTTTCCACTGCAGCGAGTGCCTCCTTTTY
GCCCCCTAGAGTGGGAAGGAAGCTGCTTTCTCATTCTGTGGTGTCTTAACCCACATCACT
ATTCAGCACAAAGGAGACACTTCTGATTCTGTCTTTGCCA Celera SNP ID: hCV11728628
Public SNP ID: rs2000252 SNP Chromosome Position: 67500143 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 105386
Related Interrogated SNP: hCV8367042 (Power = .51) SNP Source:
Celera; HGBASE; HapMap; dbSNP Population (Allele, Count): no_pop
(C,-IT,-) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 103):
ACTCCAGCCTGGGCAATAGAGCGAGACTCCATCTCAAAAAAAGCAGTGTGTGTTTCAGT
TTTAATGTATTTCAGAGACAGTATTTGATTATGTACGGCCAY
GTTTTATATAAAGAACACTTTGTTTTCCTAGAGTCTAGAAGACAGCTTGGAACATAATA
GGTGTTCCATACATTTCTGCTAAATAAAATAGTTGTTTTAA Celera SNP ID:
hCV16078411 Public SNP ID: rs2863212 SNP Chromosome Position:
67457704 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 62947 Related Interrogated SNP: hCV2990018 (Power = .51)
SNP Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(C,12|T,108) SNP Type: INTRON Context (SEQ ID NO: 104):
TGAGCAAAGCCCCTGTCTTCATGGAGCTTCTATTCTAGCCAGACAGGGCAGAAAAACAG
CAAACAAAACAAGAAGAAAAGTCAGGTGGTGGTGAAGTGTCR
TAAAGAAACATGAAGTGGGTAGGCATGGTGGCTCACATTTTGTAATCCCAGCACTTTGG
GAGGCCAAGGCAGGCAGATTGCTTGAGTCCAGGAGTTTGAG Celera SNP ID:
hCV27868367 Public SNP ID: rs4655530 SNP Chromosome Position:
67476319 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 81562 Related Interrogated SNP: hCV2990018 (Power = .51)
Related Interrogated SNP: hCV31222825 (Power = .51) SNP Source:
dbSNP; HapMap Population (Allele, Count): Caucasian (G,14|A,106)
SNP Type: INTRON Context (SEQ ID NO: 105):
TCCTTTTCTTCTGTCCTTCTCTGCCGAGCCATTCTGCCATTCTTCTGCTCTTCTATTTATCT
CTCTGTCTGCTTCTGGAACCTGGGGTCTGGAGTTTATGW
GGGTACAGGATAGCGGGGCATAGCAGGCCAAAAGGCAACTTTTGAGCACGAAAACAAG
AATGCCTGCTTCTATTTAGGGCTATGGGTTTCCAAGCTTGAG Celera SNP ID:
hCV27868368 Public SNP ID: rs4655693 SNP Chromosome Position:
67464874 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 70117 Related Interrogated SNP: hCV2990018 (Power = .51)
Related Interrogated SNP: hCV31222825 (Power = .51) SNP Source:
dbSNP; HapMap; HGBASE Population (Allele, Count): Caucasian
(A,15|T,105) SNP Type: INTRON Context (SEQ ID NO: 106):
TTTGCAATTCTAGAATCGGACAACACCTCATACTATAAAACAGAGTGAGTGTTCTGATG
AGCTGAGCAGAGGAGGTTGATTTAAGGAACTTTCTTATCACR
CTGGCGAAAACTGGCCTGTTTAGGGATTTGGCTGTTATCTCTGTGTCCTGATTTGTTGAA
AGGTCAGATAAAGATCTTAGTTTCAGCAGGTTAGTGTGGA Celera SNP ID: hCV30423493
Public SNP ID: rs7539328 SNP Chromosome Position: 67505191 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 110434
Related Interrogated SNP: hCV31222784 (Power = .51) SNP Source:
dbSNP; HapMap Population (Allele, Count): Caucasian (G,76|A,42) SNP
Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 107):
ATTCCAATGTGATAAGTAATGCCTCAACTATCTTCTATATTTGAAAATAGGGCTTTTTCA
TGTACCAGGGAGAAAGCATGATGAGCCTGGTGGGTAATATR
TGTTGAATAAATTATATTAATTATTTAAATATTTTAGGAGATTAACTCAACTTTGACATG
CAAGAAAAGCATTGGTTTTGTTTGTTTGTTTGTTTGTTTT Celera SNP ID: hCV31222830
Public SNP ID: rs12751814 SNP Chromosome Position: 67477451 SNP in
Genomic Sequence: SEQ ID NO: 14
SNP Position Genomic: 82694 Related Interrogated SNP: hCV31222826
(Power = .51) SNP Source: dbSNP Population (Allele, Count):
Caucasian (G,50|A,66) SNP Type: UTR5; INTRON Context (SEQ ID NO:
108): CCCTTATAAATATTTAAATGTCCAATCAGGTAGCCAAATGTACCTGAAGCTTTGATTGTT
TTCCCAGGAATATGGGTTTGACAAGCCAAATATTGTTTATR
ACTATTTTAGTAGTTTATAAGTCACCACACAAACATATTTAATTTGGATCATTTTATCTT
TTCCATTACAAGTCGTAAAATGCAGAACTTTTAATAATGA Celera SNP ID: hCV29503362
Public SNP ID: rs6682033 SNP Chromosome Position: 67481258 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 86501 Related
Interrogated SNP: hCV8367042 (Power = .51) SNP Source: dbSNP;
HapMap Population (Allele, Count): Caucasian (A,82|G,38) SNP Type:
INTRON Context (SEQ ID NO: 109):
CTTACCTATCTTGTGCTAGGACTTGTCTAGACATCTTCTTCAATCTTTAAAACAACCCAT
GAGATAAGTGTTACGCATCTATTTTATAATGAGGAAACTGM
AACTTAGAGTAGTTGAGGAAACTTTTCAAGGTCATAGAGCTGCTAAGTGACAGACTAAA
ATTCAAATCCTTTTCTTTCAATGTCCTGGAGTCTATTGTCT Celera SNP ID:
hCV31222834 Public SNP ID: rs11465810 SNP Chromosome Position:
67475773 SNP in Genomic Sequence: SEQ ID NO: 14 SNP Position
Genomic: 81016 SNP Source: dbSNP Population (Allele, Count):
Caucasian (A,81|C,39) SNP Type: INTRON Context (SEQ ID NO: 110):
AGGTCATTTCCATTTTATCCATTATCAATAAACTTCTTTGCATAGCTTTGTATATAAATG
GTCTTTATTCCTTTAGTTCTAAAGAAGAATTATTGCATCAR
GAGTTAAGCACCTTTTAAGATGCTGATGTATGTTGTCGAACTGCTTTTTACCGAATCTTT
AATATTGATTGCTTTTTAAAAAGGGACCTATGAAAAGACA Celera SNP ID: hDV81067815
Public SNP ID: rs41396545 SNP Chromosome Position: 67462196 SNP in
Genomic Sequence: SEQ ID NO: 14 SNP Position Genomic: 67439 Related
Interrogated SNP: hCV8367043 (Power = .51) SNP Source: dbSNP
Population (Allele, Count): no_pop (A,-IG,-) SNP Type: INTRON Gene
Number: 3 Gene Symbol: RNF145-153830 Gene Name: ring finger protein
145 Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic Sequence
(SEQ ID NO: 15): SNP Information Context (SEQ ID NO: 111):
TAATCAAGAATCTTTCAGATGCTCCTAATTGGGCTGAAAATAGCAGCTGTTTTGAAACT
GCAAAAATGAATGGTACCATAACTGTGAAATAAAAATGAACY
ATAACTTTAATGTACTTAACATTTATGTAGAATTTTATCTACCTGTTTGTGGTTGTCAGC
AGTCTTACCTGAACCAATTCTCTGTATGCAGATTTAGCAA Celera SNP ID: hCV7538686
Public SNP ID: rs1473247 SNP Chromosome Position: 158536149 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 72729 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,93|C,27) SNP Type: INTRON Context (SEQ ID NO: 112):
ATATCTTTACTTCATTTCCTTTATCCAATCCTCCATTGATGGAGACAGTCAGGTTAACTC
CATGTCTTTGCTATTGTGCATAGTGCTCTGATAAGCATATY
AGTGCAAATATCTTTTTTTATATAATTGTTTCTTTCCCTTTGGGTTTATACCCAGTAGCAG
GATTGCTGGATCAAATGGTAGTCCTATTTTTAGTTCTTT Celera SNP ID: hCV1030180
Public SNP ID: rs270659 SNP Chromosome Position: 158493420 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 30000 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,97|C,21) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 113):
CATCCTGGGCCACACGCAGCCCAGGAGTTGGACAAGCTTAGTCTACAATTTCAAAGAA
GTAACTTGCTGAGGTAACATATTTACTAGGTAAGGAAACAATY
TGTATCAAGTCTGATTCTAAAGTTAATTTTCCTTTCTACTAACCATGCTGCCTACCTAAG
TGGAATGAACTAGATTGTGAAAACATGGATTCAAGTTAAA Celera SNP ID: hCV2081970
Public SNP ID: rs1897565 SNP Chromosome Position: 158550843 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 87423 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (T,93|C,27) SNP Type: INTRON Context (SEQ ID NO:
114): GGTTACTAACAGCACTGAACATTATCAATAAGTATATGAAAACATTTGCAATTATTTGG
TGAAATGTTCACATTCTTTGCCCATTTTTCTGCTAGAATACR
TATCCTACTGCCTGATCGAAATAGTAATCCTTAGTCACATGATTGCATTTTTCTAATATG
TCCCTTGTCTTAATATTTTAAATAACTTTATTCTCTTATA Celera SNP ID: hCV2081982
Public SNP ID: rs10076782 SNP Chromosome Position: 158537541 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 74121 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,93|A,27) SNP Type: INTRON Context (SEQ ID NO: 115):
GAATGTATGTGACATGATATTTGCATTTAGCCCTTTCCAAATATTCCATAATTATAAAAT
GCTTTGTATGAATAAGCTTTTACATTATGACATCCTTGTAY
AAACTACTTGGAACACATTTCCTAATATTCTCTTAGGCTAGGAATTACTGAATCAGAAA
AAAACATTTTTAAAGACTTTGACACACTGTCAAGACTGCCC Celera SNP ID: hCV2081983
Public SNP ID: rs17663721 SNP Chromosome Position: 158537218 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 73798 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,96|C,24) SNP Type: INTRON Context (SEQ ID NO: 116):
ATTTATGAAGATTTTCCCTTTAACAATTATTTCATTAATAGAAAAGTTGTTTCATGAACT
ATTAGTATCATCTCTTAATTGTCCTCTAACTTGAGAATTAS
GACGCTTTTCCTTTCCTTTTTTAATTCCCAGTACACTGAATTGAATTCATCACAATCCTTG
ATTGACGATGTACTGTCATCATTTGTCTGTGCATGTCCC Celera SNP ID: hCV2081991
Public SNP ID: rs13178603 SNP Chromosome Position: 158524593 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 61173 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,96|C,24) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON
Context (SEQ ID NO: 117):
GCTTTCTACCAACAGATGTGCAGGGTATTTTTCCCTCTGCCCTTGTTTGTTCATTAATCCA
TGGTAGGGGACACCAATGGATGGTCACAGTTATGATTCCY
CCCATCAATGTGTTTTGCTTGGTTTTCATAGCATTTTTAATTATTTATTTTTGGAGACAGA
GTCTCATTCTGTCACCCAGGCTGGAGTACAGTGGCGTGA Celera SNP ID: hCV3220380
Public SNP ID: rs270654 SNP Chromosome Position: 158497687 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 34267 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,109|C,11) SNP Type: INTERGENIC; UNKNOWN
Context (SEQ ID NO: 118):
AGCTTGAAGAGACTAAGAGCAGGCAATCCAAGTCTCCTCCACATGTGGAAACCAAGTC
CAGAGACGGAGCAGTAACTGCCCGGCTCCCACGGCTTGTAATY
GCAGAAACAAGCTTTAAGCCGGCTGCCTCCTTCCTCGTTGCTTTTACCATTATTTAATTT
GTAGGCTTCACAAAGGCTATATGTGTTGAAATTGGCTAAA Celera SNP ID: hCV3220386
Public SNP ID: rs270661 SNP Chromosome Position: 158492732 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 29312 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (C,95|T,25) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 119):
AGTAGGACTATAATCAGAAGGAAAAAGCAGGATTTGACTTATAGGTATTCAATTCTTTA
TTATTTTTGTCTTCATTACAATAGCTAACACATATGGAACAY
TGTCTGCCTGGTACTAAACTCATTTAAATCTCACAGAACTCTATGAGGAAAGCACAGCT
TTCATTATTAGCTCCGTTTTACAGAAAGTAACGCAATTATC Celera SNP ID:
hCV11270803 Public SNP ID: rs13158488 SNP Chromosome Position:
158535849 SNP in Genomic Sequence: SEQ ID NO: 15 SNP Position
Genomic: 72429 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (T,96|C,24) SNP Type: INTRON Context
(SEQ ID NO: 120):
ATAAAAAGACACACAGTCCTCTCCTTCCCTTTCAGACTAGTTTCCTCTTTACTGCAGACT
GCGACGCAAGGCCATCCACTAATCTTTGATGCCTGCTCACY
GCACAGGCCCCTTCCTCTCTCCCCGCACCTCCTCCCACAACGCCTGCAGATCTCAGATGC
GTTTGAACTACAGTAACCCCAACCCAGCTCGCGGCAAGCA Celera SNP ID: hCV27841092
Public SNP ID: rs6556405 SNP Chromosome Position: 158567680 SNP in
Genomic Sequence: SEQ ID NO: 15 SNP Position Genomic: 104260 SNP
Source: Applera Population (Allele, Count): Caucasian (C,13|T,25)
African American (C,17|T,11) total (C,30|T,36) SNP Type: UTR5;
INTRON SNP Source: dbSNP; Applera Population (Allele, Count):
Caucasian (T,89|C,27) SNP Type: UTR5; INTRON Context (SEQ ID NO:
121): GCCAAAAATACTATTGACACAAACATGCATCACAACTCACTCTACAGCATTAACCAAAC
AATCCATAACAAACTAAGTTGACAATGGCAAAGCTGTTAGTK
TTTAAATTATACACAGTAATTTGTAATTAAAAAGCAAGACCAGTGGCATTTAAAAATGA
TGACCTAGGCCAGGTGTAGTAGTGCACACCTATAATCCCAG Celera SNP ID:
hCV30377542 Public SNP ID: rs6888950 SNP Chromosome Position:
158557329 SNP in Genomic Sequence: SEQ ID NO: 15 SNP Position
Genomic: 93909 SNP Source: dbSNP Population (Allele, Count):
Caucasian (T,90|G,24) SNP Type: INTRON Gene Number: 4 Gene Symbol:
UBLCP1-134510 Gene Name: ubiquitin-like domain containing CTD
phosphatase 1 Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic
Sequence (SEQ ID NO: 16): SNP Information Context (SEQ ID NO: 122):
GTCCACCCCCTGACAATGATGATGTTGTTAATGACTTTGATATTGAAGATGAAGTAGTT
GAAGTAGAAAATAGGTAAGTGCTTTTCGCTTTAGAAGTAATS
AGTTGTCATGTGAGAACAAGTGAATATTTTATCTAATTATATGTTTTCCATTAGGGAAGA
AAACCTACTGAAAATTTCTCGCAGAGTGAAAGAGTACAAA Celera SNP ID: hCV2084255
Public SNP ID: rs3734104 SNP Chromosome Position: 158630059 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 62850 SNP
Source: Applera Population (Allele, Count): Caucasian (C,10|G,22)
African American (C,25|G,11) total (C,35|G,33) SNP Type: INTRON;
PSEUDOGENE SNP Source: Applera Population (Allele, Count):
Caucasian (C,14|G,18) African American (C,25|G,7) total (C,39|G,25)
SNP Type: INTRON; PSEUDOGENE SNP Source: dbSNP; Celera; HapMap;
HGBASE Population (Allele, Count): Caucasian (G,53|C,67) SNP Type:
INTRON; PSEUDOGENE Context (SEQ ID NO: 123):
GGAAAGTTTTCGGAGTTTTACAGCAAGAAAAACACCATTATGTTTGATGACATAGGGAG
AAATTTTCTAATGAACCCACAGAATGGACTAAAGGTAAGACR
TACTTTTACTTGTTATGTGCTCATGTAATCTGGGCTGTGTGGTAGAACTTTTGTAGTAAG
CACTGTTGAATTTCATATATTTTTGGAAGTACTGTATTCT Celera SNP ID: hCV25633374
Public SNP ID: rs12520035 SNP Chromosome Position: 158637948 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 70739 SNP
Source: Applera Population (Allele, Count): Caucasian (A,35|G,5)
African American (A,29|G,3) total (A,64|G,8) SNP Type: INTRON SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,112|G,8) SNP Type: INTRON Context (SEQ ID NO: 124):
TTGGATCTAAATCACAAATATTGGGAAAGGTAAGTTTTAATTGCTTATTTATTTTCTCTT
TACATCAATGAAGAAAAAATTATCATTTTTCATCAGTGACY
CCAGTATATATATAGCTGTCTTAATTTTTATTTAAAATAGGTGACTTCTAAAAACATTTT
CTAATCCAGTGACCTACCCCCAAAAGTATTTTCCCCTTTC Celera SNP ID: hCV7537829
Public SNP ID: rs1433046 SNP Chromosome Position: 158642997 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 75788 SNP
Source: Applera Population (Allele, Count): Caucasian (C,10|T,24)
African American (C,17|T,5) total (C,27|T,29) SNP Type: INTRON;
PSEUDOGENE SNP Source: dbSNP; HapMap; HGBASE Population (Allele,
Count): Caucasian (C,53|T,67) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 125):
GAGAAGTATGTAAACAGCTAACTATATTTTGTTAAAGATTTATAGGAACATTTTCACAT
GACAAAGAAGTTCCCAACCACTGTGGACCCTCACTGGTGCCS
AGATGTCTGTGGTTATTGGTCATCTCTTGATCTCAACTCCCTCCTTGTCCCCTTACCCTTA
CACAAAAAGAGCCTAAAATTTGTCTTGACTTAAGATGGT Celera SNP ID: hCV1030157
Public SNP ID: rs254837 SNP Chromosome Position: 158615778 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 48569 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(G,7|C,99) SNP Type: INTRON Context (SEQ ID NO: 126):
TGTAACCACATTTTGGATTATTTCAAGGTCCAATGTGATACAAAAGTTGGAGAAATTGA
AAATAAATTTTATAAAAATTATAATGAAGAAATATACAGCAW
AGAAGAATAAAAGGGAAACAATAAAGGGTTAAAAGTACAGATTCCAGAGCTGTCCAGT
TCAGCAGCCACTAGCCACATGTGGCTATTGAGCATTTGAAAT Celera SNP ID:
hCV1030159 Public SNP ID: rs254839 SNP Chromosome Position:
158607721 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 40512 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (T,94|A,24)
SNP Type: INTRON Context (SEQ ID NO: 127):
ACAACTTGAAAACAGAAGCAATGCACCTTCAGAATTGATCCTGCCTCCCAAGAAGCCTA
CTTCCAAAGATCAGAATCATAAAATGCATTTTTGCTGTCTTY
GTAAGCAATTTTGATATTTTGTCAGTTTCATTGCTATTAAGTGATCATTCCTTGCTTCAA
ATGAAAGCTAGAGAGAATTACAATTCTTATGATACTGTTT Celera SNP ID: hCV1030161
Public SNP ID: rs254843 SNP Chromosome Position: 158605897 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 38688 SNP
Source: dbSNP; HapMap; HGBASE Population (Allele, Count): Caucasian
(C,95|T,25) SNP Type: INTRON Context (SEQ ID NO: 128):
CTTCCCGAGGTATGGAAGGATTGTGAATCTACTCAGTCAATCTTAAAAGGGGCAATGGG
GAGAGGGAAAACAAGGAACCCTCACAGGCTAATTTTTAAACY
ACATCTCTTAAGAAAATATGGAGAAGCAAAGAGAGGAAAATGTAAATTACCTGAAATT
CTACCACTGTAAATATGTTGATATACTTTCAGACTTTTTCCT Celera SNP ID:
hCV1030169 Public SNP ID: rs254850 SNP Chromosome Position:
158599309 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 32100 SNP Source: dbSNP; Celera; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,95|T,25) SNP Type: INTRON Context
(SEQ ID NO: 129):
CCTCCAGAGTTATATACAAATTGTAATCATTCATTGATATGTATTGTTACAAGCGTAATA
TGTACAGCTGGCCCTCTGGATCCACAGGTTCCAAAACTACR
GATTCAACCAACCTCGGGTTTGAAGTATTAGGGGAAAAACCCAAAGATAATAAGACAA
CAATAAAAAATAATGGAAGTAAAAGCAATACAGTATACCAAC Celera SNP ID:
hCV2081927 Public SNP ID: rs194228 SNP Chromosome Position:
158619371 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 52162 SNP Source: dbSNP; Celera; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,67|A,53) SNP Type: INTRON Context
(SEQ ID NO: 130):
TAAATAAAATATCACATCTATTATATTTACATGCATTAATAATAGCTTATTGGGAATATT
ATTATGGGAAAGTCATGAGGATAAAAAAGTTATAGTTTAGW
TTCACCATGTTTAAAATCATAATAATACGGCTGGGCGTGGTGGCTCATGCTTGTAATCCC
AGAACTTTGGGAAGGCCAAGGCGGGTGGATCACGAGGTCA Celera SNP ID: hCV2081932
Public SNP ID: rs4921200 SNP Chromosome Position: 158610802 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 43593 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,25|A,95) SNP Type: INTRON Context (SEQ ID NO: 131):
CTGGGATTACAGGCATGAGCCACCACGCCCAGCCAAGTAGGCCATCTTTTGATCCATGT
TTCAGCTAACCAAGCAAATAAATTATTAGAACCTTTTTTTAW
CTCCCTGATCTGCAACATTAAATGCAGAATCCCTGCTTAGTGGGTCCATATCAGTAAATT
CAGCCTGATCCAACTTTATGTTCTTTCCACCATTATCCCA Celera SNP ID: hCV2081943
Public SNP ID: rs254852 SNP Chromosome Position: 158596372 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 29163 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,95|A,25) SNP Type: UTR5; INTRON Context (SEQ ID NO: 132):
AGGTGAGGAGGACTGACCTTGTTAAAACACAGATTCCTAGGTCCCTTCTCTCCACCCCA
ATTACATTTCTACCAAATTACCAAGTGAGGTCAATGCTGTTS
GTTAGCCCAGGGACCATGCTTTGAAAACCACTAGTCTAGAAGAGCAATCACTTGTCCAG
GGTCACCTGGAACTCAGATGATTTCACTCCAAACTCTGCAC Celera SNP ID: hCV2084251
Public SNP ID: rs10515780 SNP Chromosome Position: 158624371 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 57162 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,25|G,93) SNP Type: INTRON Context (SEQ ID NO: 133):
CTTGTTAAAACACAGATTCCTAGGTCCCTTCTCTCCACCCCAATTACATTTCTACCAAAT
TACCAAGTGAGGTCAATGCTGTTCGTTAGCCCAGGGACCAY
GCTTTGAAAACCACTAGTCTAGAAGAGCAATCACTTGTCCAGGGTCACCTGGAACTCAG
ATGATTTCACTCCAAACTCTGCACTACTACGCATCACAATA Celera SNP ID: hCV2084252
Public SNP ID: rs10866711 SNP Chromosome Position: 158624388 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 57179 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,25|C,93) SNP Type: INTRON Context (SEQ ID NO: 134):
ATTTGTCCATTTGAAGATATTATGATTTATACTACACTGTTGTATTATAGTTTTAATTGTG
GTAAAATTGTCAGTCTAGCAATCAATGAAAAATAAAACCN
GCACCGTGAATGTGTTATTAACTGTATAAGTATAGTAGTAGCACAAATGATCAAATTTA
ATATGGTAAATCTGCCCAGGAAACATACATAACGAATTATT Celera SNP ID: hCV2084254
Public SNP ID: rs2420825 SNP Chromosome Position: 158629709 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 62500 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
no_pop (C,-IT,-) SNP Type: INTRON; INTERGENIC; UNKNOWN Context (SEQ
ID NO: 135):
ATAAGGGACTGTAGCTCGTCATTTGATGTAGTAGGATATGTAATGATTTAGAAATTTTC
ATGACACATTTAAGTGAAAGAAGTATTTTAGAGAACACTGTY
GTAAGCCGTTAGAAAATAGTTCTTAACCTTTGTTTGGTTCAGGATTACCCTTAATTTAAC
AAAGAACCTGTCAACTCTCTGAGGCTGCTCTTGTTTATAA Celera SNP ID: hCV2084259
Public SNP ID: rs7708700 SNP Chromosome Position: 158636313 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 69104 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,26|C,94) SNP Type: INTRON Context (SEQ ID NO: 136):
GCCTAGGCTGGTCTCGAGGTCCTGCACTCAAGCGATCCACCTATCTCGGCCTCTCAAAG
TGCAGGATTACAGGCATGAGCCACTGCGCCCAGCCCAGAAAK
AGTTCTAAAATGGAGAAATATCCTCAAATGCTGTGTTTTGTTATCATGCTTTCATAATGC
ACTTGGTAGAAATCTCAAAGATTTCATGTAGATCTTAAAA Celera SNP ID: hCV2084262
Public SNP ID: rs17665189 SNP Chromosome Position: 158640194 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72985 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,53|T,67) SNP Type: INTRON Context (SEQ ID NO: 137):
ATCATATTATCTAAAATTAATTTAAAATTATTGAAAGACTATCTTGAGTTGTATAAAGAT
ATTTGAGCAGGTGTCTTTTACAAAACAGCAGAATTCTTTAY
TGAAGCTATAAAATAAGGAAAAGTGCATAAATTTATAGTTCAACAAACTGTAAAGATA
ATTCTTGTAAAAAATTTTATTCCACTAAAATTACTCATGATT Celera SNP ID:
hCV2084263 Public SNP ID: rs10515782 SNP Chromosome Position:
158641855 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 74646 SNP Source: dbSNP; Celera Population (Allele,
Count): Caucasian (C,26|T,94) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 138):
TAAACTCTTTTTCATCATAAAATAGATCAGCCTTAAACATTTGGAAAATATGGCAGTTCT
TTTTATGGAAAACTCTTGCATAATTAAAAATGATTTTAACR
GAGAATTTAATGATAAAGAAAAATGCTTATGATAAAATGTAGGAGGAAACAGGTTATA
TAAATGTATAATGATATCTCAGCTATATAAAAATTTAATAGA
Celera SNP ID: hCV2084265 Public SNP ID: rs7736656 SNP Chromosome
Position: 158642268 SNP in Genomic Sequence: SEQ ID NO: 16 SNP
Position Genomic: 75059 SNP Source: dbSNP; Celera; HapMap
Population (Allele, Count): Caucasian (A,26|G,94) SNP Type: INTRON;
PSEUDOGENE Context (SEQ ID NO: 139):
TGGAATATAATCCCTCTTCTCATACTGTAACTTAATGTCAGGATAAGATAAAACACATG
TAAAAATTTCATAAATAGTATTAAAAATTACCAGTAACTTGW
GTGTAGCAGAGAAATTAGAAAAGTTTATCCTACTAAAAAAACAATTACTCATAATTTTC
CTTTTTAAAGATAACCACTGTTACCATCTTGGTATATAGTC Celera SNP ID: hCV2084266
Public SNP ID: rs10042630 SNP Chromosome Position: 158643346 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 76137 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(A,26|T,94) SNP Type: INTRON Context (SEQ ID NO: 140):
CAAAGGCCCCCTTCCATTTCTCCTCTCCAGAGTGTTCCAGTAAGAACATCCCCTTCTAGC
TATTTCACACATGGACAACCAAGAAATAGTCATTTACAGAR
CATTTTGCATTTGTACAATTTCACTCGTTATTTCTCCCCCAGTACCTAATGGGGGCTGCA
GCGTGTACTCTGTTCGTGGTTAAATTCTGCTGCCAGAAGT Celera SNP ID: hCV2084270
Public SNP ID: rs2082412 SNP Chromosome Position: 158650367 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 83158 SNP
Source: dbSNP; Celera; HGBASE Population (Allele, Count): Caucasian
(G,93|A,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 141):
TCCCATGATGGTCAAGGAATAATTTTGGAGGAGACGTTTAACTTTAAAAAAAAAAATAC
AATCATTAGTTTCATGTTTGTTTAAAAGAAACTTTGTTTTCS
TAACCAACATTTGAGCTCCATTCATCTCTTGATGCAGGGAGAGATGTTATTGTAAATGTC
TAGTTCTTTATGTTACTTTACAGTAGGGTTTTTAAAAGAC Celera SNP ID: hCV7537756
Public SNP ID: rs1368437 SNP Chromosome Position: 158639557 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72348 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (C,112|G,8) SNP Type: INTRON; PSEUDOGENE Context
(SEQ ID NO: 142):
ATAAAAAGACACACAGTCCTCTCCTTCCCTTTCAGACTAGTTTCCTCTTTACTGCAGACT
GCGACGCAAGGCCATCCACTAATCTTTGATGCCTGCTCACY
GCACAGGCCCCTTCCTCTCTCCCCGCACCTCCTCCCACAACGCCTGCAGATCTCAGATGC
GTTTGAACTACAGTAACCCCAACCCAGCTCGCGGCAAGCA Celera SNP ID: hCV27841092
Public SNP ID: rs6556405 SNP Chromosome Position: 158567680 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 471 SNP
Source: Applera Population (Allele, Count): Caucasian (C,13|T,25)
African American (C,17|T,11) total (C,30|T,36) SNP Type: UTR5;
INTRON SNP Source: dbSNP; Applera Population (Allele, Count):
Caucasian (T,89|C,27) SNP Type: UTR5; INTRON Context (SEQ ID NO:
143): AGGGAATTGTGGGGTCAGAGCCCCCATACAGAGTCCCTACTGGGGCACTGCCTAGTGG
AGCTGAGAGAAGAGGGCCACCACCCTCCAGGCCCCAGAATGGS
AGATCTGACAACAGCTTGTACTGTGTGCCTGGAAAATCCACAGACACTCAATGCCAGCC
CGTGAAAGCAGCTGGGAGGGAGGGTTTACCTTGCAAAGCCA Celera SNP ID:
hCV27883435 Public SNP ID: rs4921442 SNP Chromosome Position:
158626678 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 59469 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (C,88|G,26) SNP Type: INTRON Context (SEQ ID NO:
144): ATTCCCAAAGTGTTACTTTTACTGCTATACTTTAAAATTTCTTCATTTGCCACTTTTTAGG
TTTGTGGTCCCGGGCAAGTTTAATTTCTTTTCAGGATTCY
CATTTGTATAATGAGGACAACAGCTGTTGGTTCAGGATTGTGAAGCTTCAATGAGATAA
TTGTTTAGCATGTTTTTATTCCATCATGAACACCATTTGTA Celera SNP ID:
hCV27936085 Public SNP ID: rs4921437 SNP Chromosome Position:
158623529 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 56320 SNP Source: dbSNP; HapMap; ABI_Val; HGBASE
Population (Allele, Count): Caucasian (T,26|C,94) SNP Type: INTRON
Context (SEQ ID NO: 145):
GGATTACACAAATGTGTGAACAGCAGAAGGTAGAAACATTGAGGGTTATGGTACAGTC
TGTTTGCCACAATCCCTGAATCCATTCTTTAAAAAGTTGGTAK
AAAAATACCTACTTTAGAGGGTTGTTATGTGAATTCAAAACAAGATAACATATATCGAG
TGTTTACGTGGTACCTGGCACATAGTGAGCATTCAATAAAT Celera SNP ID:
hCV30557642 Public SNP ID: rs10056599 SNP Chromosome Position:
158655488 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 88279 SNP Source: dbSNP; HapMap; ABI_Val Population
(Allele, Count): Caucasian (T,93|G,27) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 146):
CCGATAGTGCCCACGGTGAACCCGTATTATTGTTCCTCTATCAGGTAGCTCAATATATAT
GAAAAGATAGTGGAATCTGCTAGGTGATACAGGTGAGGGAR
GATCCTTTGATTTGAGTTGATGACAGGAATTCAGCTGAGTCATGTTTTAGGATGCAGGC
TCATACCTAGAACCATCTTGAAAGTACCATCTGGGAGCAAG Celera SNP ID:
hCV31985608 Public SNP ID: rs12652431 SNP Chromosome Position:
158654672 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 87463 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (A,94|G,10) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 147):
GACTTTTCAGGAATCTAGAGGTAAATCAATTATTTAATTGAATACAAATCCCTCTTACTT
TTATTCCCAGTTCTTAATTCTCTGGAGCACTGATTGCTATY
ACTTCTTGTTGGATAATCTGTGAGGAGAACTGCTGTAGCTTCCTAAATAAGGCTTTTGAA
AGAGCCAGTGGTTTGTCAGAAAAACATGTGACTAAAATCC Celera SNP ID: hCV30629526
Public SNP ID: rs4921458 SNP Chromosome Position: 158648241 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 81032 SNP
Source: dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (T,26|C,94) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 148):
TAAATTGAAACATTATGTGGCCTTTCGTGTGGGTTCTTTAACTTAGGATAGTGTTTTCAA
GTTTCATCCATATTGTAGCAAGTATCAGCACTTCATTCCAY
TTTATGGCTGGATGACATTCCAATGTATGGGTCTGCCATATTTTGTTCATGCCATTTATC
CACTCATGGATATGTAGCTTGTTTCCACTTTCTGCCCATT Celera SNP ID: hDV70267720
Public SNP ID: rs7719425 SNP Chromosome Position: 158603516 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 36307 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,96|C,24) SNP Type: INTRON Context (SEQ ID NO: 149):
TCTGGAGCCAGGAGTTAGAATCCCTGAGTTCATCGTTTTCTTTCATCACTTTGTCCAGCA
AACTTAGGAGCAACCAAACAACTTTATGACATTCCTTGATY
CTCCACATATGGTCAAAGGTATTATGTATAGAGTCACTAAACTCCTTGCCTCTGCAGAG
CAGTGAATCAGGAGTATCAAATGCATTTATTTTGCATAACT Celera SNP ID:
hCV30431544
Public SNP ID: rs7715173 SNP Chromosome Position: 158597209 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 30000 SNP
Source: dbSNP Population (Allele, Count): Caucasian (T,96|C,24) SNP
Type: INTRON Context (SEQ ID NO: 150):
GTTTACAATGAGGATATTTTAGGGAAAGAATACTAATCTAGGTAGTGAATTGCCATAAG
TATAAAAACTGTTGACTTGGAAGAAAAGTGGTTATGTTGTCY
TTAATGGTTTCTGTTTAAGGCTTGGAGAGAAGTGCTTTTCTTAATATGTACTGCACCAGG
TAAAGGTACAAAAATGTATTCTTGAGTCTTGAGAAGAAAT Celera SNP ID: hCV2084260
Public SNP ID: rs13153734 SNP Chromosome Position: 158639291 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 72082 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
Celera Population (Allele, Count): Caucasian (C,98|T,20) SNP Type:
INTRON; PSEUDOGENE Context (SEQ ID NO: 151):
CGAAATCAGTTATTGGACTAATGATACCTATAGCAGCTCTTCAGTGTAAAAGGTAAGGA
ATGGAAAAACAGGTTGTTACAGTAAGCAACTGAAACTTATTY
TTTATTCATGGAAAGTAAAATAGTTCCTTGAGAGGAAGAGGAACTACAGGATAGGGAC
TGGGAAAAAAGGATATGCAAAAAAACGCAGATTAGTTGCATT Celera SNP ID:
hCV2084269 Public SNP ID: rs6895626 SNP Chromosome Position:
158646681 SNP in Genomic Sequence: SEQ ID NO: 16 SNP Position
Genomic: 79472 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (T,26|C,94) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 152):
TCTGGCGAATTCTACGTGAAATGTCAGGAACCAGTGAAGGGTGTTAAGCATAGAATGA
CAATCTAATTTTTTTTAACAGCCTTATTGAGATAGAATTTACM
TATCACAAATTTACCCATTTGAAGTGTGCAGTTCAATGGTTTTTAGTGTATTTAGAGAGC
TGTACAACCATCACTGTAAGCTAATTTTAGAACCTGATTT Celera SNP ID: hCV31985611
Public SNP ID: rs13161132 SNP Chromosome Position: 158649646 SNP in
Genomic Sequence: SEQ ID NO: 16 SNP Position Genomic: 82437 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
HapMap Population (Allele, Count): Caucasian (A,88|C,16) SNP Type:
INTERGENIC; UNKNOWN Gene Number: 5 Gene Symbol: hCG1979566 Gene
Name: Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic Sequence
(SEQ ID NO: 17): SNP Information Context (SEQ ID NO: 153):
CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTG
CACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAAR
CAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTG
ATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693
Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 27905 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,21|A,99) SNP Type: INTRON Context (SEQ ID NO:
154): TGGACAGATGAAGGCTGGTACTCATGCTTCTTCCCACTGCAAGAAGAGGAGCCATGTGT
CATTTCCTCTCTGTGACTGTGAGCAGCCCTTGGCCCCTGGAR
CTCCCCAGGTACAACCGGAACAACATCATGGTGCACTGGGCTTACTTTTAAGCCTAGAA
CATGAAGAGAGCTGGTTAGAAGGGGACAAGCAAAGGACTGG Celera SNP ID: hCV1994960
Public SNP ID: rs4921483 SNP Chromosome Position: 158700943 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 40425 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,19|G,99) SNP Type: INTRON Context (SEQ ID NO: 155):
TCAAAGCAGAACCTTAGGCTCTAAGGGAAACAAGACAGAAGGATTCTGCTGACAAGAC
AGTAAAGTAGCCTGCTCATCTGGTGGTAGGCACTGTGTCAGCR
TTCTAGGTTGTAAATGTAGGAAGTAAGCAGATCAGAGGTTTGCTCAACAACCTGCCTAG
TGAGCCAAACTGCTTGCTCTTGAGGCCATGTAGTCCTTCTG Celera SNP ID: hCV1994965
Public SNP ID: rs953861 SNP Chromosome Position: 158705160 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 44642 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (G,20|A,100) SNP Type: INTRON Context (SEQ ID NO: 156):
CCTGACCTTGTGATCCTCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGG
CACCGCGCCAGGCCTATTGTCTCTTTAATACCTCTCTATCAY
TTGTTGATCTCTCTTCTTAAGGAGGGCAAGCACTCTTCAGCCTTAGAGGCATTAGCAGG
CAACAGCATCTATTCTAGTGGATCTCATCCTTGGCTGCATG Celera SNP ID: hCV1994966
Public SNP ID: rs11746138 SNP Chromosome Position: 158706357 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 45839 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,108|T,12) SNP Type: INTRON Context (SEQ ID NO: 157):
TCCTGTCTTCTTTAGGCCCAGTTTCCTCAACAATGAAATGGGACTAATTATCCCAGGTCA
CACTTCTCTCTGGGCTTACCCTGGGAATCAGATGATTGAGS
TTTGGTAAGTATTATTTGATAAACAAGTATGAGGAAGGAAATAAAAGGGAGATCAGTG
CTGCAGAGATGGCTAATTGGCAGATTTACACAGAACTGGATT Celera SNP ID:
hCV1994967 Public SNP ID: rs11747112 SNP Chromosome Position:
158707187 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 46669 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (C,108|G,12) SNP Type: PSEUDOGENE
Context (SEQ ID NO: 158):
CTTCTTTATTTTCTCAACAATGTTTTGCAGTTCTCAGCATATAACTTTCATTTCTTTTGTTC
AATTTATTCCTAAGTATTTAATACTTTTTGGTGCTATTK
CAGATGAATTTTCCTATTAATTTTCATATTGGTCATTGCAATTGTATAAAAATACAATTA
TTTTTGTATATTGATCTTGTTTCATGCAATCTTGCTGTGA Celera SNP ID: hCV1994971
Public SNP ID: rs7725339 SNP Chromosome Position: 158709579 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 49061 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,73|T,35) SNP Type: INTRON Context (SEQ ID NO: 159):
ATGAGGTGCCCTGTGGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCAT
TTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTR
GCTGTTCAGTCTTTATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTAT
GCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAAC Celera SNP ID: hCV1994973
Public SNP ID: rs1157509 SNP Chromosome Position: 158718688 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 58170 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,20|G,100)
SNP Type: INTRON Context (SEQ ID NO: 160):
GGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCT
CTGAGCTCTACCTTTATGCACTGTTTTAGCTGTTCAGTCTTY
ATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATT
TGAGTTGAATTTTTGTCACATGCAACTGAGAGTCCTGACT Celera SNP ID: hCV1994974
Public SNP ID: rs1157510 SNP Chromosome Position: 158718702 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 58184 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,20|C,100) SNP Type: INTRON Context (SEQ ID NO: 161):
GAACAGATGACCAGGGGTGACTCAGGACAGAGCAGGTGACCAGGGGAACAGATGTGA
ACTGCTGATTAGAACTGGTGGAAAAAGTTGTTTACTGAAACTAY
GGGCGAGGAGAATGAGGAAGTTAAACTTTAAAATGGAGAACAAAGAACTGAACATACT
GACATACTGATTCTTTGAAGAGAAATTTAGAACTCACTGTAT Celera SNP ID:
hCV2084277 Public SNP ID: rs6874870 SNP Chromosome Position:
158662099 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 1581 SNP Source: dbSNP; Celera Population (Allele, Count):
Caucasian (T,23|C,93) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 162):
CCACTTCCAACATTGGGGATCAAATTTCAACATGAGATTTGGAGGGACAAATATGCAAA
CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTY
TGGGGTATTGAAAATATTCCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTG
TATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTG Celera SNP ID: hCV2084281
Public SNP ID: rs7730390 SNP Chromosome Position: 158663370 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 2852 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(T,91|C,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 163):
GTGATAATGTCTGGGCTTGGCAATTACCTTCAGTCTGTTCTCCTCCTGTGATACAGTTAA
TTTTTCCTAATTAATGAGATTCCTGGGGAGGAAACTCATGR
CAATTGAGTGCCTTTTTGGAAGATCTATCTTTAGGCAGACGAGGCAAGTTCAGAGACCA
CCCTTCCCTGTGCTTTTGAAACAGGGGTGAGAGACAGCAGG Celera SNP ID: hCV2084283
Public SNP ID: rs1549922 SNP Chromosome Position: 158664126 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 3608 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,63|A,53) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 164):
ACCAAGGCCAGGTAAAAACCACCCCTTCATCCCCTAAACCTTGCAAGAAGCACAGGGT
CCAGAATTATGCTTCTTTCAGGTTCTAAATAGCACAATAAAAY
TAATAACAATAAGCTTTTAGTTATTAGATCAGGTACATTTTACTTTACAGTAAGCTTTTA
CTTATTGGATCAGGTACATTTTAAAGCAATTTTTGAACAT Celera SNP ID: hCV2084288
Public SNP ID: rs6870828 SNP Chromosome Position: 158671090 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 10572 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,54|T,64) SNP Type: INTRON Context (SEQ ID NO: 165):
AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCT
ATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCK
AACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAAT
CAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293
Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15010 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,93|G,27) SNP Type: UTR3;INTRON Context (SEQ ID NO:
166): ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATA
TCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAY
CTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTT
ATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294
Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15168 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (C,117|T,3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 167):
GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAAT
GCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTY
AAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACA
GATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295
Public SNP ID: rs2195940 SNP Chromosome Position: 158676930 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 16412 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (C,110|T,10) SNP Type: INTRON Context (SEQ ID NO: 168):
GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGG
CCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGY
GAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAA
ATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296
Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 16720 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (T,26|C,94) SNP Type: INTRON Context (SEQ ID NO:
169): CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCA
GAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACM
TTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGT
CTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297
Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 19624 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,110|C,10) SNP Type: INTRON Context (SEQ ID NO: 170):
GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAA
GGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCK
TTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAG
TGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298
Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 21148 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,65|T,55) SNP Type: INTRON Context (SEQ ID NO: 171):
TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACT
TAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATY
GTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCC
ATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC
Celera SNP ID: hCV2084301 Public SNP ID: rs3213093 SNP Chromosome
Position: 158683557 SNP in Genomic Sequence: SEQ ID NO: 17 SNP
Position Genomic: 23039 SNP Source: dbSNP; Celera; HGBASE
Population (Allele, Count): Caucasian (C,93|T,27) SNP Type: INTRON
Context (SEQ ID NO: 172):
TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAA
AGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACKA
GGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGT
CCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839
Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 14074 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (G,26|T,94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 173):
GAAGTCCCACCAAGACTCCCAAGGATAGCGTGTTAGCATACAAGCTGAATAGCCTGTGT
TGCAGTCCCTGCTAGTCAGGGTCTTCTGGATAATGCATTGCM
TGTGTGAGGACTGGCCTGGTCCTCTGCAGGCTGAATTCTGCATTTAGCAGCTCAGTGTCC
CTTCCACGGGCCCCAGTTTCTTCATCAGGAAGGTGAGGGG Celera SNP ID: hCV7537857
Public SNP ID: rs983825 SNP Chromosome Position: 158707543 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 47025 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,30|A,86) SNP Type: INTRON Context (SEQ ID NO: 174):
GCTTGTCCCAAATTTCTTTCTATTTGAACTTCCTTGGTGATAAAAATTCTCCTGTGGGAG
AATTTTTGTTGTGAACATTTTGGACATTTTGTTGTGTTTGS
CTCTAGCTAAAACATGAGCATTTGTTCCTAGAAGGGATAACATTTTTACACTTCTGTTGC
CATTAGTATGTGAGCAAGAATTAATATATGAACTCATTGT Celera SNP ID: hCV7538743
Public SNP ID: rs1363670 SNP Chromosome Position: 158716689 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 56171 SNP
Source: dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (G,20|C,100) SNP Type: INTRON Context (SEQ ID NO: 175):
GGAGAGCAGGAGCAGGAGCTGGGGTGATTGCCTTTGGAAGCCATTAGGAACAAACTGT
GTACCAGCCTGTGGCAGTGTCTAGGGGTTGTCCATGACCTCTR
GAGCCCAAGGGGGCATGTGTTACAAACAATACTCTTTTAGCATTTGCTGTCCACAGACA
GCTAAGTGTTTACCCGCTCAGTGGAGGGTTGGGGTGACAGC Celera SNP ID:
hCV11269323 Public SNP ID: rs11135059 SNP Chromosome Position:
158703915 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 43397 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (G,81|A,39) SNP Type: INTRON Context
(SEQ ID NO: 176):
GGACAGTAGAGGTGCTTTCCTGTGGGATCCCCAATCTCTCCCCGCCTTCAGGTGAGTCC
TGCTGATGCTCAGGCTGCCCTTGGAACAGGGACCTTGGCCAY
AGTTTCCTTATCTGTAATAATGGGATGAGAATTCCTCCTGCACAGGGTTGTTAGGGACCT
CGTGAGGCAGCTTCTATGGCTGCCTTTGGTGCTTAGTTTT Celera SNP ID: hCV11316602
Public SNP ID: rs1865014 SNP Chromosome Position: 158671666 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 11148 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,20|C,94) SNP Type: INTRON Context (SEQ ID NO: 177):
TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGC
ACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGAR
ATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACAT
GTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290
Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 18367 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,93|A,27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE;
INTRON Context (SEQ ID NO: 178):
GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCA
GTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGR
CTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACT
TGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID:
hCV15894459 Public SNP ID: rs2546892 SNP Chromosome Position:
158688053 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 27535 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,103|A,17) SNP Type: INTRON Context
(SEQ ID NO: 179):
GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGC
AGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAY
GAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTT
CATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID:
hCV29927086 Public SNP ID: rs3213094 SNP Chromosome Position:
158683347 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 22829 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,93|T,27) SNP Type: TRANSCRIPTION
FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 180):
CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTC
CTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAM
CGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGT
GAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID:
hCV31985602 Public SNP ID: rs3213119 SNP Chromosome Position:
158676366 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 15848 SNP Source: dbSNP; HapMap; HGBASE; Population
(Allele, Count): Caucasian (C,115|A,1) SNP Type: MISSENSE MUTATION;
INTRON Context (SEQ ID NO: 181):
AACAAGGGGCTTCTTGAGAGGAAATGAAAGGAGACGGAGATGCGGTTTTGCCTTAAGG
TTTTTAATGTGAGCCACTGAGAAGATTCATTTTGAAATAGAAR
GATGTGTCTGACAGTGTGATGTAAATGCAGGCATTTTGGAGTCCCTGCTGGAGAACACA
CAGAGGTGAGTAGGGGTTCTCCAGTGACCTTGTGGGAGTCT Celera SNP ID:
hCV27106385 Public SNP ID: rs4244437 SNP Chromosome Position:
158705695 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 45177 SNP Source: dbSNP; Celera; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,31|A,87) SNP Type: INTRON Context
(SEQ ID NO: 182):
CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTG
TCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTR
TGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATAC
TCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID:
hCV27106395 Public SNP ID: rs11574790 SNP Chromosome Position:
158676424 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 15906
SNP Source: dbSNP; Celera; HapMap; Population (Allele, Count):
Caucasian (G,110|A,10) SNP Type: INTRON Context (SEQ ID NO: 183):
TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATG
AAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCR
TATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAA
TGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID:
hCV27467944 Public SNP ID: rs3181224 SNP Chromosome Position:
158673428 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 12910 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (A,110|G,10) SNP Type: INTRON Context
(SEQ ID NO: 184):
GTAGTGGCTAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAA
AACTCTGCATTGCATGCACTGAAATTAATCGAATGCTAAGAGR
TCATGTCGCAAAAGCACTGGGCATGGTGGGAGCCAGAACATCTCACCTCTGCCCCAGGC
TGGCCAGAAATTTGGGGAAAGGTCCCAGTTCTCAGTGCTTA Celera SNP ID:
hCV27467945 Public SNP ID: rs3181225 SNP Chromosome Position:
158673201 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 12683 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,102|A,18) SNP Type: INTRON Context
(SEQ ID NO: 185):
GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGAC
GGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAAS
TCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAG
GCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935
Public SNP ID: rs3212217 SNP Chromosome Position: 158687708 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 27190 SNP
Source: dbSNP; HapMap; HGBASE Population (Allele, Count): Caucasian
(G,93|C,27) SNP Type: INTRON Context (SEQ ID NO: 186):
TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACA
GAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCM
TTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATA
GAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507
Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 26521 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(C,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 187):
GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTG
TCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTM
CCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAA
AGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID:
hCV27508808 Public SNP ID: rs3212218 SNP Chromosome Position:
158687174 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 26656 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,81|A,25) SNP Type: INTRON Context
(SEQ ID NO: 188):
AATGAACAGAAAATGGAAGTGAGGTACAGAGACAGCTTGGTTGGTTACAGCTAGGTGT
TTGCTTTATTTGAGCATGGTCTGATCAGTTGGTAACCTATAAY
TGATTGGAGGTTTGCTGCTGTGTTTTACTGCTGAGGCTCAGCTATTAGCTACAAAAATAT
ATTAAATTAGCTTTCAGTCAGTTCATACCAAGTTAGGTTG Celera SNP ID: hCV28001193
Public SNP ID: rs4921466 SNP Chromosome Position: 158665350 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 4832 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(T,112|C,8) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 189):
AGTTGGATTCCCCAAAATAATTAGTTAGTTAATTTGTTGACTGATTGATTGACACATTGC
TAGCTCCTCTCAGACTGCCCAGTCTTCCTCATGCCCAAAGK
GCTCTCATTCTGTTCATGATAACGCCCAAAATCTTTACCTTGGCACACTCGTTTCTCCAT
GATCTGCCCCTACTCCCTAATCGCTGTCACCTCCTACAAT Celera SNP ID: hCV29349406
Public SNP ID: rs6556411 SNP Chromosome Position: 158715801 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 55283 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(G,32|T,88) SNP Type: INTRON Context (SEQ ID NO: 190):
CTGTATGCCCAGCAAAGGGCTGGTGGCTGGAAGGACATAGCTTTCTGAGTTAGGACTGG
AAGGCTTCTGTACATGTCCAAAGTCAACCTTCATATTCATGR
GGAGGGAAAAAGAAGTGGGCTTTAGGATTGCCTCTCCTTGTTGGCCTGCTCTGAGAAAA
ACAATCGCGGGAGGGTGAGGCGGGAGAATCGCTTGAGCCCA Celera SNP ID:
hCV29349409 Public SNP ID: rs6859018 SNP Chromosome Position:
158669570 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 9052 SNP Source: dbSNP Population (Allele, Count):
Caucasian (G,91|A,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 191):
CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCA
ACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGM
ACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAG
GAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID:
hCV30449508 Public SNP ID: rs3212220 SNP Chromosome Position:
158686773 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 26255 SNP Source: dbSNP; HapMap; ABI_Val; HGBASE
Population (Allele, Count): Caucasian (C,93|A,27) SNP Type: INTRON
Context (SEQ ID NO: 192):
TACTACAGGGGAGAACACTGGTGGACAGACACAACCTAAACAAAGTGATCAAAGTTAA
TTTCACCAGTACTGAGAGACATTGATTTCATGCCCCTCCTGAY
GAGATTCACTGAGAAGGGCACAGTATTACTGCTGTAGGATGCTTGACAAAAATGTAGA
ACCCAAATTTAATCATGAAGAAACATGAGACAAATGTCACTT Celera SNP ID:
hCV29619986 Public SNP ID: rs10072923 SNP Chromosome Position:
158668354 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 7836 SNP Source: dbSNP; HapMap Population (Allele, Count):
Caucasian (T,93|C,27) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 193):
TAAATAAAATAAAATAAAGTAGAAAAGAAACAAAAATTATAAGATAGGGACATTAAAT
GGAGTTAGAAATGAGGCTAATAAATAATGAATATGCTGCACCR
TGGAATACTACTCAGCCATAAAACAGAACAAAATAATGGACTTTGCAGCAACTTGGAT
GGAGCTGGAAGCCATTATCTTAAGTGAAATAATTCACAAATG Celera SNP ID:
hCV31985582 Public SNP ID: rs6556412 SNP Chromosome Position:
158719963 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 59445 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (G,79|A,39) SNP Type: INTRON Context (SEQ ID NO:
194):
CATTCTCATTTAAATTTGTATATCCCTGATTATTTTTGAGGCCAGGCACCTTCTCAGTCTA
TCAGTTATCTGTTAAGTTTTGAATCGATTTGTCCATTGGY
TGTCTTACCTTATTGATTGGTAGAAGCCCTTAATTTTGGCATGAGCTCTTTATTAGTTAC
ATGTGTGGCAAATATTTTCTCCCACTCAGGGACTTGCTGT Celera SNP ID: hCV30611467
Public SNP ID: rs6869411 SNP Chromosome Position: 158714182 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 53664 SNP
Source: dbSNP; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,71|C,49) SNP Type: INTRON Context (SEQ ID NO: 195):
ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCC
AGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCR
TCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTT
TAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748
Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 29028 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,94|G,26) SNP Type: INTRON Context (SEQ ID NO: 196):
ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGA
GAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCY
GAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCC
TGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592
Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 36237 SNP
Source: dbSNP; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,76|C,44) SNP Type: INTRON Context (SEQ ID NO: 197):
AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGT
ACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTW
TGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGA
CCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID:
hDV75439995 Public SNP ID: rs3213097 SNP Chromosome Position:
158681257 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 20739 SNP Source: CDX; dbSNP Population (Allele, Count):
Caucasian (T,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 198):
GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATG
TGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGAG/TTAGA
CCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATG
CCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID:
hDV79877074 Public SNP ID: rs17860508 SNP Chromosome Position:
158692783 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 32265 SNP Source: dbSNP Population (Allele, Count): no_pop
(G,-1,-) SNP Type: INTRONIC INDEL Context (SEQ ID NO: 199):
CCATATCAGGTGTTGATGGTGAAGGGGTGCTGTGTTTCTTTTTGGGGTATTGAAAATATT
CCAGAATTTATTGTGGTGATGGGAGCACAACTCTGTAAGTS
TATAAAACCTGTTGAATTAGACACCTTAAAAGAGTCACTTGTAGAGTATGTGAACTATA
CCTCATTACAGCTGTTAGAAAAATGTATACCTTGGTGGTCA Celera SNP ID: hCV2084282
Public SNP ID: rs2099327 SNP Chromosome Position: 158663429 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 2911 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
Celera; HGBASE Population (Allele, Count): Caucasian (G,100|C,20)
SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 200):
AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGC
CCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCK
CCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAA
CCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051
Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 15463 Related
Interrogated SNP: hCV15894459 (Power = .51) Related Interrogated
SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; HGBASE
Population (Allele, Count): Caucasian (T,102|G,18) SNP Type:
TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 201):
TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACC
ATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACY
CTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCC
TTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID:
hCV15879826 Public SNP ID: rs2288831 SNP Chromosome Position:
158682591 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 22073 Related Interrogated SNP: hCV2084270 (Power = .51)
Related Interrogated SNP: hCV2084293 (Power = .51) Related
Interrogated SNP: hDV71045748 (Power = .51) SNP Source: dbSNP;
HapMap; ABI_Val; HGBASE Population (Allele, Count): Caucasian
(T,91|C,25) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON
Context (SEQ ID NO: 202):
TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAAC
GATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAY
AGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTG
GCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033
Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 23309 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
HapMap; HGBASE Population (Allele, Count): Caucasian (C,102|T,18)
SNP Type: INTRON Context (SEQ ID NO: 203):
TCACAAGTCTGTTATGTAACCATAGTTGGGACTGGAGTCTGCTCCTCTGATTCCCAGTCC
TAAGATCTTTGGCTTAGACATTTAGTACATTTTGTAGTGGS
TAGATTTACAATAAAAAGGACAGTCCTGGAGACTATCTTTAAAGAAGAAAAACTCTGC
ATTGCATGCACTGAAATTAATCGAATGCTAAGAGGTCATGTC Celera SNP ID:
hCV27467946 Public SNP ID: rs3181226 SNP Chromosome Position:
158673108 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 12590 Related Interrogated SNP: hCV15894459 (Power = .51)
Related Interrogated SNP: hCV27467945 (Power = .51) SNP Source:
dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (G,102|C,18) SNP Type: INTRON Context (SEQ ID NO: 204):
TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGA
AAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAW
GGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATG
GGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID:
hCV32389155 Public SNP ID: SNP Chromosome Position: 158681347 SNP
in Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 20829
SNP Source: HGBASE; dbSNP Population (Allele, Count): no_pop
(A,-IT,-) SNP Type: INTRON Context (SEQ ID NO: 205):
TACCTCCCAACAGTCCTGTGAATTTACTATGCTACCCCAGGGTGACCTGGTAGAGAGTT
TGGAACCACAGCTAGCCATAGTACTTTCAAACTACTAAAGTY
AGATATCTCTTTGCCACCAAATCCCTCCTCAGGGCCATATGTGACCCTGCATTTTGTGCA
GGGATTCCAGGAAGCAAAGTTGTCACTCTTTCTGGAAACT Celera SNP ID: hCV31985590
Public SNP ID: rs11738529 SNP Chromosome Position: 158702844 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 42326 Related
Interrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP;
HapMap Population (Allele, Count): Caucasian (T,64|C,46) SNP Type:
INTRON Context (SEQ ID NO: 206):
AGTGACAATTACATATCAGGCACCCAGCTAAATTCTGTGAATGTAGTAAGCAGATCAGA
CCTGGACTCTGTCCTCATAGAGCTAAATAGATATGTGCAGAR
GACAAAATGCTATGAAGGAAATGAATGGGTGGTGAGACAGAGAATCACAGGGGAGGG
CTCTCTGATGAGGTGGCATTTAAGTTGGGACCTACAGGTGAAC Celera SNP ID:
hDV70836316 Public SNP ID: rs17056705 SNP Chromosome Position:
158701831 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 41313 Related Interrogated SNP: hCV11314640 (Power = .51)
SNP Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(G,112|A,8) SNP Type: INTRON Context (SEQ ID NO: 207):
CCTGCCAGAAGGCAATTAAAGAGTGGAAGAGCAGAAATGCAGAGAAGGAATTCAACA
CCTGCTCCACCAGCACGTTCCTTGGTCGCTCTCGTCTGTTTCCY
TAGCTGGATCACATTCTTGGTGAATGAGAGAAAGTATGAGGATTAATGAGCAGACCTGT
CTTTGGGATACCCTAGAACCATGATGCAATGCAAATATCAC Celera SNP ID:
hDV70836317 Public SNP ID: rs17056706 SNP Chromosome Position:
158703333 SNP in Genomic Sequence: SEQ ID NO: 17 SNP Position
Genomic: 42815 Related Interrogated SNP: hCV30611467 (Power = .51)
SNP Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(C,69|T,49) SNP Type: INTRON Context (SEQ ID NO: 208):
GGATGAGTCTCACTTAGTCATGAAATGCAGTCTCTTTGTATGTTGCTGGATTTAGTTTGC
TAGTACTTTGTTGAGAATTTGTGCCTCCATATTCTTAAGTR
ATTTTGGTCTGCAGTTTTTTTTTTGAGATGTGTTTGTCTGGTTTTGATATCAGGGTAATAC
TAATTTCATAGAATAAGTTAAGAAGTGTTTCCTCCTCTT Celera SNP ID: hCV31985588
Public SNP ID: rs6878967 SNP Chromosome Position: 158711610 SNP in
Genomic Sequence: SEQ ID NO: 17 SNP Position Genomic: 51092 Related
Interrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP;
HapMap; ABI_Val Population (Allele, Count): Caucasian (A,71|G,49)
SNP Type: INTRON Gene Number: 6 Gene Symbol: hCG2038173 Gene Name:
Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic Sequence (SEQ
ID NO: 18): SNP Information Context (SEQ ID NO: 209):
CTGTGTGCCCAGCACTTCCTCTGCATGCCTCAGATGCATTTGACAATCTCAGGTGAACTG
CACTTCAGGGTCAAGGGAACCCCGGCCATGGTTCTAAGAAR
CAACTCCCATTTTAGTATCACCTACATTTGAAACCACAGAGCACTGTCCAGGAGAGGTG
ATGGTGGTGGGTCTCCTCCTTTGGCTCTCTGGCCCATCAGC Celera SNP ID: hCV1992693
Public SNP ID: rs1433048 SNP Chromosome Position: 158688423 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 15090 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,21|A,99) SNP Type: INTRON Context (SEQ ID NO:
210): TGGACAGATGAAGGCTGGTACTCATGCTTCTTCCCACTGCAAGAAGAGGAGCCATGTGT
CATTTCCTCTCTGTGACTGTGAGCAGCCCTTGGCCCCTGGAR
CTCCCCAGGTACAACCGGAACAACATCATGGTGCACTGGGCTTACTTTTAAGCCTAGAA
CATGAAGAGAGCTGGTTAGAAGGGGACAAGCAAAGGACTGG Celera SNP ID: hCV1994960
Public SNP ID: rs4921483 SNP Chromosome Position: 158700943 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 27610 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,19|G,99) SNP Type: INTRON Context (SEQ ID NO: 211):
TCAAAGCAGAACCTTAGGCTCTAAGGGAAACAAGACAGAAGGATTCTGCTGACAAGAC
AGTAAAGTAGCCTGCTCATCTGGTGGTAGGCACTGTGTCAGCR
TTCTAGGTTGTAAATGTAGGAAGTAAGCAGATCAGAGGTTTGCTCAACAACCTGCCTAG
TGAGCCAAACTGCTTGCTCTTGAGGCCATGTAGTCCTTCTG Celera SNP ID: hCV1994965
Public SNP ID: rs953861 SNP Chromosome Position: 158705160 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 31827 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (G,20|A,100) SNP Type: INTRON Context (SEQ ID NO: 212):
CCTGACCTTGTGATCCTCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGG
CACCGCGCCAGGCCTATTGTCTCTTTAATACCTCTCTATCAY
TTGTTGATCTCTCTTCTTAAGGAGGGCAAGCACTCTTCAGCCTTAGAGGCATTAGCAGG
CAACAGCATCTATTCTAGTGGATCTCATCCTTGGCTGCATG Celera SNP ID: hCV1994966
Public SNP ID: rs11746138 SNP Chromosome Position: 158706357 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 33024 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,108|T,12) SNP Type: INTRON Context (SEQ ID NO: 213):
TCCTGTCTTCTTTAGGCCCAGTTTCCTCAACAATGAAATGGGACTAATTATCCCAGGTCA
CACTTCTCTCTGGGCTTACCCTGGGAATCAGATGATTGAGS
TTTGGTAAGTATTATTTGATAAACAAGTATGAGGAAGGAAATAAAAGGGAGATCAGTG
CTGCAGAGATGGCTAATTGGCAGATTTACACAGAACTGGATT Celera SNP ID:
hCV1994967 Public SNP ID: rs11747112 SNP Chromosome Position:
158707187 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 33854 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (C,108|G,12) SNP Type: PSEUDOGENE
Context (SEQ ID NO: 214):
CTTCTTTATTTTCTCAACAATGTTTTGCAGTTCTCAGCATATAACTTTCATTTCTTTTGTTC
AATTTATTCCTAAGTATTTAATACTTTTTGGTGCTATTK
CAGATGAATTTTCCTATTAATTTTCATATTGGTCATTGCAATTGTATAAAAATACAATTA
TTTTTGTATATTGATCTTGTTTCATGCAATCTTGCTGTGA Celera SNP ID: hCV1994971
Public SNP ID: rs7725339 SNP Chromosome Position: 158709579 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 36246 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,73|T,35) SNP Type: INTRON
Context (SEQ ID NO: 215):
ATGAGGTGCCCTGTGGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCAT
TTCCATTTCTGGTCTCTGAGCTCTACCTTTATGCACTGTTTTR
GCTGTTCAGTCTTTATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTAT
GCTCTTGGGTAATTTGAGTTGAATTTTTGTCACATGCAAC Celera SNP ID: hCV1994973
Public SNP ID: rs1157509 SNP Chromosome Position: 158718688 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 45355 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,20|G,100) SNP Type: INTRON Context (SEQ ID NO: 216):
GGGGTTAAACAGAAATGAGAGATGCAAAGAGTGTAAGGTGGCATTTCCATTTCTGGTCT
CTGAGCTCTACCTTTATGCACTGTTTTAGCTGTTCAGTCTTY
ATCTAAATAACTTCTAATAACTCCACTGCCACCGCCATCTAGCTATGCTCTTGGGTAATT
TGAGTTGAATTTTTGTCACATGCAACTGAGAGTCCTGACT Celera SNP ID: hCV1994974
Public SNP ID: rs1157510 SNP Chromosome Position: 158718702 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 45369 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,20|C,100) SNP Type: INTRON Context (SEQ ID NO: 217):
AAAAAACAAATAATTGCATCAAAAAGTGGGCAAGAGACATGAATAGCGAATTCTCAAA
AGAAAATATACAAACAGCCACCAAACATATGAAAAAATGCTCR
ACATCACTAATTATCAGGGAACTGCAAATTAAAACCACAATGAGATACCACCTTACTCA
TGCAAGAATGGCCATAATTAAAAAGTCAAAAAATAATAGAT Celera SNP ID: hCV1994986
Public SNP ID: rs11749573 SNP Chromosome Position: 158743793 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 70460 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (G,20|A,100) SNP Type: INTERGENIC; UNKNOWN Context (SEQ
ID NO: 218):
CACTAATATGAGAACAATCTCTTTAGGACTGGAAACCACGAAGTCAATTGAATTGAATG
CACCACAACCCAGTGAGTTAAATCTTTGTGGAAAGATTCCAS
AAATGCCTCTAAAGTTGCATCTATAAGCTTAATGATCTTATGTCTGTGTCTCCATGGATG
CCAAGTGATATGATTTGGATCTCTATCCCCACCCAAATCT Celera SNP ID: hCV1994990
Public SNP ID: rs6861600 SNP Chromosome Position: 158752193 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 78860 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(C,82|G,38) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 219):
CTGACTTGCTTCATACTTCTTCCTGCCTCCGCTAGCCTCCACCCAGGGAAGGTGTGCTTC
TCGGTAAGTCAGTTTGAGAGAAGCAGTGTAGTGTAGTGGTS
AATAGTCTGGATTTACATCTTTGATCTTCCATTTACTACGCTTGTGACCTAGGGGGTGTT
GCTTCCCCTCTCTGTTCCAATTATTTATCCATAAAATAGA Celera SNP ID: hCV1994992
Public SNP ID: rs6887695 SNP Chromosome Position: 158755223 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 81890 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (G,82|C,38) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 220):
TAAATTTCCAACTCATGCCTTTTGGGGGACACATTCAAACTATAGCAAATACTAAGTTA
AGGAAGTTTCAGCTCTGTCTGGCAGCCTCATAATATTTCAAY
GCTTCATCATTTGAATGCTTATTAATTAACCAACTTCCTGTATGCCATGTGATCAGATGT
CACAAGAGGAGTTCCTTTGGGATGAACTTAGTTCTTTGTG Celera SNP ID: hCV1995017
Public SNP ID: rs4921496 SNP Chromosome Position: 158780649 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 107316 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (T,27|C,93) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 221):
GCTGGAATTCAGATCCCAGGTCTGTCAAAGCCTAATCCCAGCCAGCCTTCCTTCTGTTGC
TCCAACGGGGAGTCCTACTCAAAACTGTTCCTGGTCCTGTR
TGACAGCATTGATAAGACTCCTGGAAATTTTTGTTACTTCCTAGCCTCCACTTTCTACCT
TCCCATTTTCTCCTAATTTTCTCAATCTTTGTTGGGGTTT Celera SNP ID: hCV1995018
Public SNP ID: rs4921500 SNP Chromosome Position: 158783091 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 109758 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,27|G,93) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 222):
CTGGTTCTTTCCCATCAGTGCTGTCACCAAAGAGAACCACCATTTTCATATTATCTGTTT
TCGAACTCATATAAATGGAATCGTAGAGCATGCGTTCATTK
TGTCTAACTTCTTTTGTTCAAAATTATGTCTGGGAGATTCATCCATGTTCTAGCATGTAG
GAGCCGCCCACCCTTTTTCATTGCTGTGTAGTATTCTGTT Celera SNP ID: hCV1995024
Public SNP ID: rs7702534 SNP Chromosome Position: 158790051 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 116718 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(T,26|G,90) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 223):
AAGTCATAAAGCTGAAGAAACTTCTGGGTGTTCAGTGAGTAAATGAATGTTTGAGTGCA
ATGTGGAGACAGAATCATCATTGCACGTCTTATTTATAATTM
GGATTGTTCATCAGGTTGACCTTGAATCATGGATCCCATAACAGAAAGTTAGATACGGC
TGCTTTGAGAACTAAAAGGCCCAAAAAGTGCAGTCAGATCC Celera SNP ID: hCV1995530
Public SNP ID: rs2421186 SNP Chromosome Position: 158850858 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 177525 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,84|C,28) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 224):
AATTACTTAAATATTTAAATAGCATGAAGGCCCATGGCAACTTGAGAGCTGGAAAATCT
ATACATAAATTAGCTGATTGTTTCAATGAGCATTTAGCATCK
AACTATACAAATACAGCAAAGATATCATTGTGATCCTAAAAAAACGTTTTAAAGCAAAT
CAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTT Celera SNP ID: hCV2084293
Public SNP ID: rs3212227 SNP Chromosome Position: 158675528 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2195 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (T,93|G,27) SNP Type: UTR3; INTRON Context (SEQ ID NO:
225): ATCAGATAGAAATTATCTTTTTGGGTCTATTCCGTTGTGTCTTTAAACATTTTGCTTAATA
TCTTCCACTTTTCCTCCAAATTTTCATCCTGGATCAGAAY
CTGGAAGAGAATGCCAAAAGTTGATGTGGGGTGACATTGTAACAGCAATGTCTCTTCTT
ATTTCTCACAACATATGATCCTGGGCAACTGGGTTTCAGGG Celera SNP ID: hCV2084294
Public SNP ID: rs3213120 SNP Chromosome Position: 158675686 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2353 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (C,117|T,3) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 226):
GGAAAATGTCTTAGGTTCTCTGTGTCTGTTTCCTCACTTATAAATAGGGATAACAATAAT
GCCTACTTCATAGAATTATAGTTCAAGGTAAAAATCACGTY
AAACTCTTAGCAAGTCTTTAGCACATAGGAAGCACTCAATATCACCTATTAGTCATACA
GATCTTAAATAGGGAAAGTACTTGCCAAGATGTAAAATAAT Celera SNP ID: hCV2084295
Public SNP ID: rs2195940
SNP Chromosome Position: 158676930 SNP in Genomic Sequence: SEQ ID
NO: 18 SNP Position Genomic: 3597 SNP Source: dbSNP; Celera;
HapMap; HGBASE Population (Allele, Count): Caucasian (C,110|T,10)
SNP Type: INTRON Context (SEQ ID NO: 227):
GGCTTTGTCCAGTGATTTTAAAAGTGGGGTGAAAGGAGTCTGGGGCGGTACAAAAGGG
CCTCTGGAACCTTGCAACAGGCAAAGGAATTCTGCTGTAAGGY
GAGGAAGCTGGGAAGCCAATATCTTAGCCTCTATAAGTGTAGACATTCTGTTTAGTAAA
ATAATTTTATAATATCTGGAACAGCCAGGAGCTATCCATTT Celera SNP ID: hCV2084296
Public SNP ID: rs2853696 SNP Chromosome Position: 158677238 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 3905 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (T,26|C,94) SNP Type: INTRON Context (SEQ ID NO:
228): CCCCTCTGACTCTCTCTGCAGAGAGTGTAGCAGCTCCGCACGTCACCCCTTGGGGGTCA
GAAGAGCTGAAGTCAAAGACAGAAATTAGCCTGTGTTACACM
TTGGGGAGAGAGTTCCTAGTGATTGTAGCCAGTAAGGCAGGTAAGGCCTCAACTGTTGT
CTGAGGACACAGTTTCTCCAACTGGGCTGATTTCTACCCAG Celera SNP ID: hCV2084297
Public SNP ID: rs919766 SNP Chromosome Position: 158680142 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 6809 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,110|C,10) SNP Type: INTRON Context (SEQ ID NO: 229):
GTCTGCTTCAGGGCCCCTAAGATCTACGCCCTGGAGCTCTTGTTTTTATTTTTGACTCAA
GGTGCAATTTCAGCAAGTCATTTGTAGCTTTGAATTCTCCK
TTTATCCCTTTCTTTGGTGCTATGAGGCTTCAGGAAGCATGGCCAGGCAATTTGGATGAG
TGGGTTCAAACACAGCAGAGACTATTCTCAGTTCCCAATA Celera SNP ID: hCV2084298
Public SNP ID: rs2853694 SNP Chromosome Position: 158681666 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 8333 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,65|T,55) SNP Type: INTRON Context (SEQ ID NO: 230):
TATCTGCCTTACATTTGACTGAGGATTAAATGAAAAAAAAAAAAAGCACGTAAAGTACT
TAGCACAGTGTCTGCCACACAGTAAATTCGGTGTTAGTTATY
GTTACTTATAGACTGAGGAGTCAGCCAACTGTACAGAGAAACTCTCTTAACAATTTTCC
ATGGATATTTAAGGATTTCGTTCCCTCTGTTTTAAATCACC Celera SNP ID: hCV2084301
Public SNP ID: rs3213093 SNP Chromosome Position: 158683557 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 10224 SNP
Source: dbSNP; Celera; HGBASE Population (Allele, Count): Caucasian
(C,93|T,27) SNP Type: INTRON Context (SEQ ID NO: 231):
GTGAGGGTCCAGAAACTTGTATGATCCAGGTATTCGTTTATTGATTTTTTTTCAAGTAAT
TAGTGAGCATTTACCATGTATGAAGTGCTGAGGATAAATAR
TGAGCAAGGCAAGCAGGCTTCTGCCCTCACAAAGCTCATATTCTAGTCCTGCGTATGTG
TGTTGGTGGGGGAAATGTAAACAATATACAAGTAAACAAAC Celera SNP ID: hCV3169817
Public SNP ID: rs4921499 SNP Chromosome Position: 158781130 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 107797 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (A,26|G,92) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 232):
TTCATGGAGCCATATTTTCTGGTCATAATTGTGTATCAGGTTCATTCATGCTAATGAGAA
AGGGATTCCAGATTTTCTTTGCATCTGTCTGCTTCTCACAK
GGCTGTTAAGAAGCCACCTGCCATTCTGACAATTTCATGTCCTTAGCCATAACTACTTGT
CCTCTCTCTTGAATCTTAAGATCTTTTTGCCTTCCAGACA Celera SNP ID: hCV7537839
Public SNP ID: rs1368439 SNP Chromosome Position: 158674592 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 1259 SNP
Source: dbSNP; Celera; HapMap; HGBASE; Population (Allele, Count):
Caucasian (G,26|T,94) SNP Type: MICRORNA; UTR3; INTRON Context (SEQ
ID NO: 233):
GAAGTCCCACCAAGACTCCCAAGGATAGCGTGTTAGCATACAAGCTGAATAGCCTGTGT
TGCAGTCCCTGCTAGTCAGGGTCTTCTGGATAATGCATTGCM
TGTGTGAGGACTGGCCTGGTCCTCTGCAGGCTGAATTCTGCATTTAGCAGCTCAGTGTCC
CTTCCACGGGCCCCAGTTTCTTCATCAGGAAGGTGAGGGG Celera SNP ID: hCV7537857
Public SNP ID: rs983825 SNP Chromosome Position: 158707543 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 34210 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(C,30|A,86) SNP Type: INTRON Context (SEQ ID NO: 234):
GCTTGTCCCAAATTTCTTTCTATTTGAACTTCCTTGGTGATAAAAATTCTCCTGTGGGAG
AATTTTTGTTGTGAACATTTTGGACATTTTGTTGTGTTTGS
CTCTAGCTAAAACATGAGCATTTGTTCCTAGAAGGGATAACATTTTTACACTTCTGTTGC
CATTAGTATGTGAGCAAGAATTAATATATGAACTCATTGT Celera SNP ID: hCV7538743
Public SNP ID: rs1363670 SNP Chromosome Position: 158716689 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 43356 SNP
Source: dbSNP; HapMap; ABI_Val; HGBASE Population (Allele, Count):
Caucasian (G,20|C,100) SNP Type: INTRON Context (SEQ ID NO: 235):
TGCTTACTAGAGACCAAAATGCCAAGATTTCAACGGGAGCCAGCCACCCTGGTTTCTAT
TTTGATGTGATTACTTAGTCATTTAAAGTCAGGTTAATGTTS
GCCAACAACAGATGGGGTCAGGACACAGGAGTTCTGCAGCTCACTGAAACTGGACAGT
CTTTTAGGGCACCCAGCTCACAAGGCCACACCGTGGCCCGCC Celera SNP ID:
hCV7538755 Public SNP ID: rs918520 SNP Chromosome Position:
158758888 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 85555 SNP Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE
Population (Allele, Count): Caucasian (C,20|G,100) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 236):
TGTTTTAGGATCAAAATAATGAAAAAGAATAGAAACCATTTCAACTCAGAAAATAATTC
AAAGATGGGAAAAAGGTGTGTACCAAATTCATTGCTCTAATY
ATTTCTGTTCTGATAAAAGGAGTTTACAGCAAAGGAATAACTTTTCTGTGTCTCTGAGGC
TTTGGAAAAACAAGGCATCAAGAAGCTTTGGGGTGTGGTG Celera SNP ID: hCV7538761
Public SNP ID: rs1422878 SNP Chromosome Position: 158771795 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98462 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (C,68|T,52) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 237):
GGTAAACCATGGATGTGGTTCTACAGATGTTGCCACAACAGGAAGACAAAATCTCACA
GCTAACAGAGGTCACAGCTTTTGGAAACAGTGGTTGCGACACR
GAGGAAACTCCCCCTCCCAGCCCTACCCCAAGCACATCCTTGCTTCTCTCAGTCACGCC
AGTTACACCAACAGGGGCAGCTCTGGGGAGGACATTTGGAA Celera SNP ID: hCV7538765
Public SNP ID: rs1422877 SNP Chromosome Position: 158772090 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 98757 SNP
Source: dbSNP; Celera; HapMap; HGBASE
Population (Allele, Count): Caucasian (A,57|G,51) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 238):
CCATTTCAACTCAGAAAATAATTCAAAGATGGGAAAAAGGTGTGTACCAAATTCATTGC
TCTAATCATTTCTGTTCTGATAAAAGGAGTTTACAGCAAAGR
AATAACTTTTCTGTGTCTCTGAGGCTTTGGAAAAACAAGGCATCAAGAAGCTTTGGGGT
GTGGTGGGTGTGGTGGGGCAGCCTACTGCTTGTTGAGGTAA Celera SNP ID:
hCV11264606 Public SNP ID: rs1984811 SNP Chromosome Position:
158771830 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 98497 SNP Source: dbSNP; Celera; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,20|A,76) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 239):
CTTTGTAATGTGCTATTGAATTTGATTTGCTAGTATTTTGTTGAGGATTTTTGCATCTATG
TTCATCAGGAATATTGATCTATAGTTTTATTTTTTTGCTR
TGTCCTTGTCTGGTTTTGGTATTAGGGTGATATTGATCTCATAGCATGAATTAGGGATAA
TTCCTTCCTCCTCAATTTTTTTTTAATAGTTTCAGGAAGA Celera SNP ID: hCV11264637
Public SNP ID: rs6864071 SNP Chromosome Position: 158733765 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 60432 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (G,81|A,39) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 240):
GGAGAGCAGGAGCAGGAGCTGGGGTGATTGCCTTTGGAAGCCATTAGGAACAAACTGT
GTACCAGCCTGTGGCAGTGTCTAGGGGTTGTCCATGACCTCTR
GAGCCCAAGGGGGCATGTGTTACAAACAATACTCTTTTAGCATTTGCTGTCCACAGACA
GCTAAGTGTTTACCCGCTCAGTGGAGGGTTGGGGTGACAGC Celera SNP ID:
hCV11269323 Public SNP ID: rs11135059 SNP Chromosome Position:
158703915 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 30582 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (G,81|A,39) SNP Type: INTRON Context
(SEQ ID NO: 241):
TTTGGGTGGCCTCAGCTTCCTTTTTTTTTTCTTTGTATATTCTAAGTGGATGCTTGAAGTC
ATTTCATTTATTGACATTGTCAGAATCAAAATGTGGTGAY
ATGAAATCAGTCAGGGCCAAAGTTGTTGTACTCAGAAACGTAGTATAAATCATGCAAAC
ACTATATAAAGCACATTTCAAATGAATCAGGTATTTAAAAC Celera SNP ID:
hCV11314640 Public SNP ID: rs1833754 SNP Chromosome Position:
158751505 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 78172 SNP Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE
Population (Allele, Count): Caucasian (T,112|C,8) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 242):
TTAATGGTTATGGGCCATGCATTGAAGGACCACCCTGTCTGTGCTAATCCCTCACTTTGC
ACTGAACATGGAACTAAGCTGAGCCTCTCCCTGGGGATGAR
ATGATAGATTTTCTATTTACTGCCCTTTCTTTTGTCTTTTCATAGCTTTTGGTGCGGACAT
GTCTTGGAGCAGTTACAGTCAATTGTCTCTATGCTCAAT Celera SNP ID: hCV15803290
Public SNP ID: rs2421047 SNP Chromosome Position: 158678885 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 5552 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,93|A,27) SNP Type: TRANSCRIPTION FACTOR BINDING SITE;
INTRON Context (SEQ ID NO: 243):
GCTCATTTGCTGTTGAGCAGTGGGAGCAACTTGTTGGCCAAGTTACTCGCTGAGCCTCA
GTCTCTTTGTCTATAAAATGGACCTAATACTTATCTCAAAGR
CTTGTTGGGAAAGGCAATGAGATAACATATTATAGAAGGCAACCAATAACATATTAACT
TGAACCTAGAGGAAGAGGTAAGGGAACAATTCGGTATCTGT Celera SNP ID:
hCV15894459 Public SNP ID: rs2546892 SNP Chromosome Position:
158688053 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 14720 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,103|A,17) SNP Type: INTRON Context
(SEQ ID NO: 244):
GAGAAACTTCCAGCACAATTTCAGTTTCATAGAGAATACGGCAGGGCACAATATTCAGC
AGAGTAACATAGTGGTTAAAAGCTCAGGGTGTCGAGAACAAY
GAACCAAGACTGTCATCCTGTCTCCACTAACCAGCTGGGGGATTTGGAACAAGGTATTT
CATTATCATGAGCCTCAGTTTCCTCATCTGTAAAATGATAA Celera SNP ID:
hCV29927086 Public SNP ID: rs3213094 SNP Chromosome Position:
158683347 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 10014 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,93|T,27) SNP Type: TRANSCRIPTION
FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 245):
CTCACCTAACTGCAGGGCACAGATGCCCATTCGCTCCAAGATGAGCTATAGTAGCGGTC
CTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGAM
CGTGGCTGAGGTCTTGTCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTGT
GAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCT Celera SNP ID:
hCV31985602 Public SNP ID: rs3213119 SNP Chromosome Position:
158676366 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 3033 SNP Source: dbSNP; HapMap; HGBASE; Population
(Allele, Count): Caucasian (C,115|A,1) SNP Type: MISSENSE MUTATION;
INTRON Context (SEQ ID NO: 246):
CCAATACAGGAGAGAGCTGAAGGGAATTCCCAGGCTGATGGTGAAAGATGGCCCACAA
TGACAGCTGTTTGGCAGGTCTAGAAACCCATTACAGGTTGAAR
GGAAAAGGTGGAAGTCTCCACGGTGGATGTTCCTAAGAAGAGTGGAACTGAGAGACTA
CTAATGGATTCAGGTATATTGAGAGAAATTCTTAGGGCTCCA Celera SNP ID:
hCV27106331 Public SNP ID: rs12657996 SNP Chromosome Position:
158836891 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 163558 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (G,72|A,26) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 247):
TAAGGCTTCCAGTCAATAGAAGGCTGTTATTAGTTAAGTTCTGGCTGAGTCAAAAGTGA
TACATAAATTTTCAACTGCATGGTGGGGTCAACATTACTAAM
CCCCTCACCCTTCATGGGTGAACTGTATTTTTATATCTATATCTAATCTATATATCTATAT
ATCTCTCTATATATATTTAGTTTGGGTGGCCTCAGCTTC Celera SNP ID: hCV27106358
Public SNP ID: rs6556416 SNP Chromosome Position: 158751323 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 77990 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(A,32|C,86) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 248):
ATGATTTATGAAGAAAAAGAGGTTTAATGGACTCACAGTTCCACGTGGCTGGAGAGAG
CTTACAATCATGGTGGAAGGTGAAGGAGGAGCAAAGCCATGTY
GTACATGGAGGCAGGCAAGAGAGTGTGTGCAGGGGAACTTCCCTTTATAAAGCCATCG
GATCTCGTGAGACTTATTCGCTATCACGAGAAGAGCATTGGA Celera SNP ID:
hCV27106359 Public SNP ID: rs12522665 SNP Chromosome Position:
158750818 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 77485 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (C,76|T,34) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 249):
TATTGGCCTGAAGCCTGAATCATCAACTCAGTAAATAAAATACTGGGAACAATTAAACA
AATAAAGTGAATACTATGAGAGAATGAGATAAGCCTCAAGAK
ATTGCTACCATTCCAGCCCCATAGGACACAGTGAACTGGCCCACACTCCAAGTACCTAA
CTACTACAACCAGAGCACAAAGACTCTCTATGATAAAGGAA
Celera SNP ID: hCV27106365 Public SNP ID: rs4379175 SNP Chromosome
Position: 158737506 SNP in Genomic Sequence: SEQ ID NO: 18 SNP
Position Genomic: 64173 SNP Source: dbSNP; Celera; HapMap; ABI_Val
Population (Allele, Count): Caucasian (G,81|T,39) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 250):
AACAAGGGGCTTCTTGAGAGGAAATGAAAGGAGACGGAGATGCGGTTTTGCCTTAAGG
TTTTTAATGTGAGCCACTGAGAAGATTCATTTTGAAATAGAAR
GATGTGTCTGACAGTGTGATGTAAATGCAGGCATTTTGGAGTCCCTGCTGGAGAACACA
CAGAGGTGAGTAGGGGTTCTCCAGTGACCTTGTGGGAGTCT Celera SNP ID:
hCV27106385 Public SNP ID: rs4244437 SNP Chromosome Position:
158705695 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 32362 SNP Source: dbSNP; Celera; HapMap; HGBASE Population
(Allele, Count): Caucasian (G,31|A,87) SNP Type: INTRON Context
(SEQ ID NO: 251):
CCTGGGCCCGCACGCTAATGCTGGCATTTTTGCGGCAGATGACCGTGGCTGAGGTCTTG
TCCGTGAAGACTCTATCTTTCTGCAAAAGAGAAGGAAAGCTR
TGAAGACCCCTTGGCAACATAGTCACAGGGTAAGCTGAGCCTGTTTCTGCAATGCATAC
TCTCCCAAAACAAGCCCATCTTGGTCTTAGGGCACTGTGCT Celera SNP ID:
hCV27106395 Public SNP ID: rs11574790 SNP Chromosome Position:
158676424 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 3091 SNP Source: dbSNP; Celera; HapMap; Population
(Allele, Count): Caucasian (G,110|A,10) SNP Type: INTRON Context
(SEQ ID NO: 252):
TAAAAATCTGGTTAGTGTTGTTCATTAAATGTCCGTTAAGTACTTTGGTAACTGCAGATG
AAAGACCCTGTAGGGGGACAAACACTTGTTATTAACAACCR
TATGCTGTCAAGTGTGGGCTTATAACACGGGACCATATGCTCCAAAGGTTGGCAAAGAA
TGACAGAAGCCACCCACCATTCCTCCAGGCCAGGAGCAGAG Celera SNP ID:
hCV27467944 Public SNP ID: rs3181224 SNP Chromosome Position:
158673428 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 95 SNP Source: dbSNP; HapMap; HGBASE Population (Allele,
Count): Caucasian (A,110|G,10) SNP Type: INTRON Context (SEQ ID NO:
253): GCAATGCTCAACTGTTTCAGTCAAATACCTTAAAAATGAGCATTCCTGGGTTGGGTGAC
GGAATATTGACAAATTACAGCTTTGTCAGAACTGCTACTAAS
TCTAGGCGGACCTTGCTATGTACTTTATTCCCTTATAAAGTTTGTGAGTGGCAGAGACAG
GCCTAGAAGTCAAGCCTTCTTGGACACTGCTCAGTGCTGT Celera SNP ID: hCV27471935
Public SNP ID: rs3212217 SNP Chromosome Position: 158687708 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 14375 SNP
Source: dbSNP; HapMap; HGBASE Population (Allele, Count): Caucasian
(G,93|C,27) SNP Type: INTRON Context (SEQ ID NO: 254):
TGTGTGCTGGAGCACCCAGAACTGAAGGACTTGGGTTAGGGACAGGAACGGTAATACA
GAGGCGAACTTTCAGGTTCTGGCAACGACCTGGTCACCAGCCM
TTGCTGTAGGGGTTTAGCTTCTCTTGTTTTCCAAGTTCAAAGACTACTCTCTCCCATATA
GAGAACCTAGTGGTTCTAAAATTTGAGTGACTGTCAGGAT Celera SNP ID: hCV27486507
Public SNP ID: rs3212219 SNP Chromosome Position: 158687039 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 13706 SNP
Source: dbSNP; HGBASE Population (Allele, Count): Caucasian
(C,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 255):
GTTCAAAGACTACTCTCTCCCATATAGAGAACCTAGTGGTTCTAAAATTTGAGTGACTG
TCAGGATAACCTGGAAGCACTGCTACAACAGACGGCTGAGTM
CCACCCCCAGAGTGTCTGATTCAGCAGGCATGAGGGCCTGAGAATATGCATTTCTAGAA
AGTTTCCAGGGGAAGCAGATGCTGCTGGCGCTAAGACCACA Celera SNP ID:
hCV27508808 Public SNP ID: rs3212218 SNP Chromosome Position:
158687174 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 13841 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,81|A,25) SNP Type: INTRON Context
(SEQ ID NO: 256):
GAATGGATAGCAAACGCACAGGCTCTGGAGTGGGAGCAAGCTTGGTGTGTTGAGGGAT
AGAAATACACAGAGCATGGCAAATACAGCAAGTGGTGTGAAAY
GGGGTTGGAAAAGGTGGCGCAGGCCAGATCACTAGGACCAAGGAGTTTGAAATTTATT
CCTAGTGCAGTATATCAGGTTGTATTTTTATCACTGGATAAT Celera SNP ID:
hCV27883430 Public SNP ID: rs4921493 SNP Chromosome Position:
158768685 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 95352 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (T,64|C,50) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 257):
ATCCTCAGAAGTGGGCGGCAGAGAAGGAGGAACGTGCTTGAGTCGCAGTCCCCAAAAA
GGGAGGAACTCATTGGCCCAGCTTAGGCCTGGTGTCTGCCTAY
CTGTGGTTCAGTCAGCTGTGGTCGGTGGGCAGGACACACCTGAAGGAGCATATCTTGGC
TGTGTGGGTTGGGCAGACATCCCACAATGCTCATGTAGGGG Celera SNP ID:
hCV28024675 Public SNP ID: rs4921230 SNP Chromosome Position:
158812974 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 139641 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (C,88|T,30) SNP Type: DONOR SPLICE SITE;
TRANSCRIPTION FACTOR BINDING SITE Context (SEQ ID NO: 258):
GTGGTCTGAACGTTTATGTCTCCCTAAAATTCATATGTTGAATTCCTAACCCCCAAGGTG
AGAGTGTTGGGAGGTGGAGCCTTTTAGTCTCCTGGCTGGGM
TTAGTGGCCTGATAACATAGACTCCAGAGAGCTGGCTTATTCCTTCCACTATGTGAGGA
CACAGCAAGAAGCCGCTGTCTGTGGGGAAACAGAGGCTTAC Celera SNP ID:
hCV29349404 Public SNP ID: rs7704367 SNP Chromosome Position:
158754071 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 80738 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (A,75|C,37) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 259):
AGTTGGATTCCCCAAAATAATTAGTTAGTTAATTTGTTGACTGATTGATTGACACATTGC
TAGCTCCTCTCAGACTGCCCAGTCTTCCTCATGCCCAAAGK
GCTCTCATTCTGTTCATGATAACGCCCAAAATCTTTACCTTGGCACACTCGTTTCTCCAT
GATCTGCCCCTACTCCCTAATCGCTGTCACCTCCTACAAT Celera SNP ID: hCV29349406
Public SNP ID: rs6556411 SNP Chromosome Position: 158715801 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 42468 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(G,32|T,88) SNP Type: INTRON Context (SEQ ID NO: 260):
CTCTTATTTTTAAGATGAGAAACTTAAAGCTTAGAGAAGGAATGTGACTTTCTGGATCA
ACATCTAGCAGTTGTTTATTTAGTGCTTACTACATAAAGAGM
ACTGGGCTAGAAGCAGTTGAGAGAGAAAAAAAGGGCTTACCTGGATCCCGCTTCCTAG
GAGCAAATACTTTTACTCAATAAATATTTATTAAGTCAGTGT Celera SNP ID:
hCV30449508 Public SNP ID: rs3212220 SNP Chromosome Position:
158686773 SNP in Genomic Sequence: SEQ ID NO: 18
SNP Position Genomic: 13440 SNP Source: dbSNP; HapMap; ABI_Val;
HGBASE Population (Allele, Count): Caucasian (C,93|A,27) SNP Type:
INTRON Context (SEQ ID NO: 261):
ATGTCACCAACAAGAGGCTACCCCCTGGGGAAACCTAACAGGAAAAAGGTAGTTGAGC
CAGGAAAAGCCACCAGACCCTTTCTCTTGGCTTGAGGCATCAY
ATACATTTGAATAATAATCAAATTAACAATGTAATATGACTGTTTAGCAACAATGATGT
GCTAATCATGGTTTTACATGGATTATCTTTAGTCATTAAAT Celera SNP ID:
hCV31985570 Public SNP ID: rs12651787 SNP Chromosome Position:
158772323 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 98990 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (T,64|C,50) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 262):
TAAATAAAATAAAATAAAGTAGAAAAGAAACAAAAATTATAAGATAGGGACATTAAAT
GGAGTTAGAAATGAGGCTAATAAATAATGAATATGCTGCACCR
TGGAATACTACTCAGCCATAAAACAGAACAAAATAATGGACTTTGCAGCAACTTGGAT
GGAGCTGGAAGCCATTATCTTAAGTGAAATAATTCACAAATG Celera SNP ID:
hCV31985582 Public SNP ID: rs6556412 SNP Chromosome Position:
158719963 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 46630 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (G,79|A,39) SNP Type: INTRON Context (SEQ ID NO:
263): CATTCTCATTTAAATTTGTATATCCCTGATTATTTTTGAGGCCAGGCACCTTCTCAGTCTA
TCAGTTATCTGTTAAGTTTTGAATCGATTTGTCCATTGGY
TGTCTTACCTTATTGATTGGTAGAAGCCCTTAATTTTGGCATGAGCTCTTTATTAGTTAC
ATGTGTGGCAAATATTTTCTCCCACTCAGGGACTTGCTGT Celera SNP ID: hCV30611467
Public SNP ID: rs6869411 SNP Chromosome Position: 158714182 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 40849 SNP
Source: dbSNP; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,71|C,49) SNP Type: INTRON Context (SEQ ID NO: 264):
GTTATTTTTTCTTCTTACAAAAGTTGTTATTCAAGGATTATTAGCAGCCACCATTAATTA
GGCACTTCATTATACTGTTTTACTTACCTCATACTCACCCR
ATTATTGAAGCAGGGATTCCTGCCCTAGGATTATAGGGATGGCCGACACTTGACACTTG
ACACTGAACAGATGAGATTGACAGCAGCTTGTCAGTCACAC Celera SNP ID:
hCV30017148 Public SNP ID: rs9313808 SNP Chromosome Position:
158753422 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 80089 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (A,22|G,98) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 265):
AAAGAACGTTATTGATGGAAATTTAGGGGTGTTTGGGGAATATTACTAAAATTTGTGTG
TAACCAAATTTGTGACCTTCTAACAAATGTCCCCCTGTAGAS
CTGTGAGAAACAATATTAGGGTTGACCCACTCAGTTCATGCTTTTTTTTTTTTCTGTTAA
AAAAAGCCAGCATTTCAAGCAGTGAGTAGACCAGTAAGCT Celera SNP ID: hCV32389145
Public SNP ID: rs4921504 SNP Chromosome Position: 158840941 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 167608 SNP
Source: dbSNP; HapMap; HGBASE Population (Allele, Count): Caucasian
(C,89|G,31) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 266):
ATAGCTTTTCATTTTTTAACTGGGGCCAAAGTTAGTTAATCCACAAGAATGGGGATCCC
AGCTGTCATTTTGGTTGATATCACAACTGACGACCAAGACCR
TCACAAATATGGGAGCAAGTCTGATTTGTAACATTATTATAATTATGAATCCAATTACTT
TAAGGAATGCACGAAAGGCTTTTTAAAAATTTCAATAGTA Celera SNP ID: hDV71045748
Public SNP ID: rs6894567 SNP Chromosome Position: 158689546 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 16213 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(A,94|G,26) SNP Type: INTRON Context (SEQ ID NO: 267):
ACAGACCTAGTTAGACCATAGTCCATATTTCAAATATAATTACATGTGCTCATAGCTGA
GAACCTTCTCCTGGGATGGATGCATTTCACCAGGTCACTGCY
GAAATGTTGTACTTTTATGGATGGTGATGAGGAAGCATCTGTTTTAGGTGTGGTATTTCC
TGGAGGCAGAAAACTGCTTGAGTTAGCTCATTCAGTTTTT Celera SNP ID: hCV31985592
Public SNP ID: rs7709212 SNP Chromosome Position: 158696755 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 23422 SNP
Source: dbSNP; HapMap; ABI_Val Population (Allele, Count):
Caucasian (T,76|C,44) SNP Type: INTRON Context (SEQ ID NO: 268):
AAAACATATGGGTTGGGTTATCCACTTCAATGACTGCACATTAAGCAAGAGTATAGTGT
ACCATGTTTTATTTAACCATTCCTCTGCTGATTATGTCTTTW
TGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGAAAAAGTGAGA
CCCCAATGCTTAATTTACTCAGTGAAATAATGGTAAAGTCA Celera SNP ID:
hDV75439995 Public SNP ID: rs3213097 SNP Chromosome Position:
158681257 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 7924 SNP Source: CDX; dbSNP Population (Allele, Count):
Caucasian (T,89|A,27) SNP Type: INTRON Context (SEQ ID NO: 269):
GTGATTCAGATCTGGGATGGGGCTCAGGAACCTGCATTTTAACAATGGAGGTTCTAATG
TGGTCATTGGCAGGTTGTTCTAATGTGGGGGCCACATTAGAGC/TTAGA
CCTCTCTCGGAGACAGGCTGTACATGGCCAGCCAGCATTCTGGTAATATGAGCCAAATG
CCCATTGACCTAATTTTGGAGAAGAGGTTTATCAACATGTC Celera SNP ID:
hDV79877074 Public SNP ID: rs17860508 SNP Chromosome Position:
158692783 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 19450 SNP Source: dbSNP Population (Allele, Count): no_pop
(GC,-ITTAGA,-) SNP Type: INTRONIC INDEL Context (SEQ ID NO: 270):
TTATCAATTCTTCATTTCATGGATTGTGTCTTTGGTGTTATATCTAAAAAGTCATCACCA
AACGCTAGATCATCTAGATTTTATTCTATGTTATGATCTAR
GAGTTTTATAGGTTCACATTTTATATTTAGGTCTGTGAATTAGTTTTTGTGAAAACTGTA
AGGTCTGTGTCTAGTTGATGTTCAGTTATTCTAATATCAT Celera SNP ID: hCV7538744
Public SNP ID: rs1422880 SNP Chromosome Position: 158748197 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 74864 Related
Interrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP;
Celera; HapMap; HGBASE Population (Allele, Count): Caucasian
(G,112|A,8) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 271):
TAATACATATAATACAGAAAATATCTGTTAATTGGCTATACTATTCATAAGGCTTCCAGT
CAATAGAAGGCTGTTATTAGTTAAGTTCTGGCTGAGTCAAR
AGTGATACATAAATTTTCAACTGCATGGTGGGGTCAACATTACTAAACCCCTCACCCTT
CATGGGTGAACTGTATTTTTATATCTATATCTAATCTATAT Celera SNP ID: hCV7538751
Public SNP ID: rs1422879 SNP Chromosome Position: 158751276 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 77943 Related
Interrogated SNP: hCV11314640 (Power = .51) SNP Source: dbSNP;
Celera; HapMap; HGBASE Population (Allele, Count): Caucasian
(A,111|G,7)
SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 272):
ACTGAGGACAAACTAGGGAGTGGTGGGGACCACAGTGAACCCATGGCGCATGCTCTTT
CCCAGAGGCAGGTCGCTCCTCAGATCCAGCTGACTGTGCCAGM
TGTGAAAGCAAGATGGGCATCACAGTTCTTGTGATGTTTAGAGAAGAGCTGGAAAACT
GAACTTAAATGTGAAGTAGCTATTTTAAAGGCTGGCCACAAT Celera SNP ID:
hCV7538752 Public SNP ID: rs1363669 SNP Chromosome Position:
158754724 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 81391 Related Interrogated SNP: hCV11314640 (Power = .51)
SNP Source: dbSNP; Celera; HapMap; HGBASE Population (Allele,
Count): Caucasian (A,111|C,7) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 273):
AATATCTGATTGTGTTACTTCCTTGCTGAAAACCCTTCAGTGGGTTTCAGGGCCCGGGGC
CCCCAGAACAAGATTCTGAGTCCTGCAAGCTTGCAAGTCCK
CCATGCTCTGCCTCCTGGCTACCTCTCTCTTTTCTTTGCCTTTCTCTTTAGGAGGCCAGAA
CCCCGGTCTGTTTTCTTTCCTGCAATATCCCTGTGGCCA Celera SNP ID: hCV15824051
Public SNP ID: rs2853697 SNP Chromosome Position: 158675981 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 2648 Related
Interrogated SNP: hCV15894459 (Power = .51) Related Interrogated
SNP: hCV27467945 (Power = .51) SNP Source: dbSNP; HapMap; HGBASE
Population (Allele, Count): Caucasian (T,102|G,18) SNP Type:
TRANSCRIPTION FACTOR BINDING SITE; INTRON Context (SEQ ID NO: 274):
TGGAGGTTAACATCAATTAACATCAATAAGAGACTTGATGTTAATTCATTACACTCACC
ATGACTTGGCTTTTCAATTTGTTGTTGTTGTTGTTTTTAACY
CTTATGAGCGAAAGAGAAAATTGATACTATCCAAGGGTATAGAATTACCTTTCTGGTCC
TTTAAAATATCAGTGGACCAAATTCCATCTTCCTTTTTGTG Celera SNP ID:
hCV15879826 Public SNP ID: rs2288831 SNP Chromosome Position:
158682591 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 9258 Related Interrogated SNP: hCV2084270 (Power = .51)
Related Interrogated SNP: hCV2084293 (Power = .51) Related
Interrogated SNP: hDV71045748 (Power = .51) SNP Source: dbSNP;
HapMap; ABI_Val; HGBASE Population (Allele, Count): Caucasian
(T,91|C,25) SNP Type: TRANSCRIPTION FACTOR BINDING SITE; INTRON
Context (SEQ ID NO: 275):
TGAAGCAGTCCAGTAGAGCTTAGTCTTCCCATTTAATGAAGAAGCGTACTGAGGCCAAC
GATCTAAGCATGGTCACAGCAAGTCAGAAGTACAAGGGCTAY
AGCTCAGACCTTTTGTCTCTTGGGCTTTGCAAGGGATGCCTAATGCTAGTGTCTAAACTG
GCCTTTGAGGAATGGCTTAGTATAGTATTTCAGAGTGTGT Celera SNP ID: hCV16044033
Public SNP ID: rs2569254 SNP Chromosome Position: 158683827 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 10494 Related
Interrogated SNP: hCV27467945 (Power = .51) SNP Source: dbSNP;
HapMap; HGBASE Population (Allele, Count): Caucasian (C,102|T,18)
SNP Type: INTRON Context (SEQ ID NO: 276):
AGAGTTCTAATTCACTAAACAAAACCTCAGTATACACCAAAATAGAACCTCCTTAAAGC
ATAAATCTCACATGCCCTGCAAAACAGTAACGCAATGAAAAR
AACAAAGTATCTAGGCAACAACTAACATGATGAATAGAACAGCACCTCACATCTCCAT
ATTAACTTTGAATGTAAATGGCCCAAATGCTCCACTTGAGAG Celera SNP ID:
hCV27106364 Public SNP ID: rs4262088 SNP Chromosome Position:
158738822 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 65489 Related Interrogated SNP: hCV11314640 (Power = .51)
SNP Source: dbSNP; Celera; HapMap Population (Allele, Count):
Caucasian (A,112|G,8) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID
NO: 277):
TTATGTCTTTATGCACTTGGAGAAACATTTCTTTAGTAAGCATTTTCCTTTTAAAGATGA
AAAAGTGAGACCCCAATGCTTAATTTACTCAGTGAAATAAW
GGTAAAGTCAGGATGATCACCTGGGGTTTGCTTCGGTGATGATTAAAGTAAGCCACATG
GGGGTTAACACATAGGTCTTGTATTTATGGAAGTTGCTTTC Celera SNP ID:
hCV32389155 Public SNP ID: SNP Chromosome Position: 158681347 SNP
in Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 8014 SNP
Source: HGBASE;dbSNP Population (Allele, Count): no_pop (A,-IT,-)
SNP Type: INTRON Context (SEQ ID NO: 278):
TACCTCCCAACAGTCCTGTGAATTTACTATGCTACCCCAGGGTGACCTGGTAGAGAGTT
TGGAACCACAGCTAGCCATAGTACTTTCAAACTACTAAAGTY
AGATATCTCTTTGCCACCAAATCCCTCCTCAGGGCCATATGTGACCCTGCATTTTGTGCA
GGGATTCCAGGAAGCAAAGTTGTCACTCTTTCTGGAAACT Celera SNP ID: hCV31985590
Public SNP ID: rs11738529 SNP Chromosome Position: 158702844 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 29511 Related
Interrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP;
HapMap Population (Allele, Count): Caucasian (T,64|C,46) SNP Type:
INTRON Context (SEQ ID NO: 279):
AGTGACAATTACATATCAGGCACCCAGCTAAATTCTGTGAATGTAGTAAGCAGATCAGA
CCTGGACTCTGTCCTCATAGAGCTAAATAGATATGTGCAGAR
GACAAAATGCTATGAAGGAAATGAATGGGTGGTGAGACAGAGAATCACAGGGGAGGG
CTCTCTGATGAGGTGGCATTTAAGTTGGGACCTACAGGTGAAC Celera SNP ID:
hDV70836316 Public SNP ID: rs17056705 SNP Chromosome Position:
158701831 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 28498 Related Interrogated SNP: hCV11314640 (Power = .51)
SNP Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(G,112|A,8) SNP Type: INTRON Context (SEQ ID NO: 280):
CCTGCCAGAAGGCAATTAAAGAGTGGAAGAGCAGAAATGCAGAGAAGGAATTCAACA
CCTGCTCCACCAGCACGTTCCTTGGTCGCTCTCGTCTGTTTCCY
TAGCTGGATCACATTCTTGGTGAATGAGAGAAAGTATGAGGATTAATGAGCAGACCTGT
CTTTGGGATACCCTAGAACCATGATGCAATGCAAATATCAC Celera SNP ID:
hDV70836317 Public SNP ID: rs17056706 SNP Chromosome Position:
158703333 SNP in Genomic Sequence: SEQ ID NO: 18 SNP Position
Genomic: 30000 Related Interrogated SNP: hCV30611467 (Power = .51)
SNP Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(C,69|T,49) SNP Type: INTRON Context (SEQ ID NO: 281):
GGATGAGTCTCACTTAGTCATGAAATGCAGTCTCTTTGTATGTTGCTGGATTTAGTTTGC
TAGTACTTTGTTGAGAATTTGTGCCTCCATATTCTTAAGTR
ATTTTGGTCTGCAGTTTTTTTTTTGAGATGTGTTTGTCTGGTTTTGATATCAGGGTAATAC
TAATTTCATAGAATAAGTTAAGAAGTGTTTCCTCCTCTT Celera SNP ID: hCV31985588
Public SNP ID: rs6878967 SNP Chromosome Position: 158711610 SNP in
Genomic Sequence: SEQ ID NO: 18 SNP Position Genomic: 38277 Related
Interrogated SNP: hCV30611467 (Power = .51) SNP Source: dbSNP;
HapMap; ABI_Val Population (Allele, Count): Caucasian (A,71|G,49)
SNP Type: INTRON Gene Number: 7 Gene Symbol:
Chr1:67490910..67543062
Gene Name: Chromosome: 1 OMIM NUMBER: OMIM Information: Genomic
Sequence (SEQ ID NO: 19): SNP Information Context (SEQ ID NO: 282):
TCTGGCAAAGAGAAGGCCACACACCAGGAAGCCCCTGAGGGTACAGGGACATTACTGA
TTATAAAGGAGGGAAGGAACAAGCTATGTGTGTTCCTGATAAM
CCCTGGCCCTCGGGATTGGCTGTCAAGGGGCTCAAAACCCAGTCCAAGGGACAAACAC
ATCATCCAAGCCTTGCAATGCAGTGATGTAAGTGCAATGATA Celera SNP ID: hCV261080
Public SNP ID: rs10889675 SNP Chromosome Position: 67494804 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 3894 SNP
Source: dbSNP; Celera; HapMap; ABI_Val Population (Allele, Count):
Caucasian (C,105|A,15) SNP Type: INTRON Context (SEQ ID NO: 283):
CAGTGGAAATAAATATTTGATGTTATTTTCAATAAATTGTTACTGGAGTTAAACCTCTTG
CTATCCTGACAATTCCTCCCTACATCACCCTCTTTGCAATR
GCAGATGGAAGAATTGGCAATAAATGCAATTCAGCTTGAAGAAAACACCCTAAATATT
AGAAACCTGTGAAGAACCACCGGATTGCCTTATCAACTCATT Celera SNP ID:
hCV2720238 Public SNP ID: rs11209032 SNP Chromosome Position:
67512680 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 21770 SNP Source: dbSNP; Celera; HapMap Population
(Allele, Count): Caucasian (G,83|A,37) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 284):
GACTAGAAATTGAGGCTATACCTGCAATGGGAGCAATGTACCTGCCTTTGTCCCAACTC
AGGGGAAAAATTCAAGCTGCTTTATCACAATGCAAACTTCGY
GGGGGAGAAAGGGTTTCTTTCTATAATTCTTGTATTCAAGAAGGATTCATTGAACTACT
GAATGTCCTTACTGTTATATGTGCAAGGCCATTTGAAGGAT Celera SNP ID: hCV2720250
Public SNP ID: rs4655531 SNP Chromosome Position: 67500366 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 9456 SNP
Source: Celera;HGBASE;dbSNP Population (Allele, Count): no_pop
(C,-IT,-) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 285):
GTGCAATCTCGGCTCACTGCAACCTCCATCTCCTGGGTTCAAGTGATTCTCATGCCTCAG
CCTCCCAAGTAGCTAGGAATACAGGCACACACCACCATTTS
CAACTAATTTTTATATTTTTGGTGGAGACGGGATTTCACCATGTTGGCCAGGCTGCTCTT
GAGCTCTTGGCCTCAAGTGATCTGCCTGTCTTTGCCTCCC Celera SNP ID: hCV8367042
Public SNP ID: rs1008193 SNP Chromosome Position: 67492499 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 1589 SNP
Source: dbSNP; Celera; HapMap; HGBASE Population (Allele, Count):
Caucasian (G,82|C,38) SNP Type: INTRON Context (SEQ ID NO: 286):
TTGAGTATTTCTAAGCTGCTCGATAGATTAGAGTTGTTTGGTGTGGCAGTTCCCCAGTGT
GTCCAGTTGCTCACAAATTTTGACTTGAATGTTCTTTGCCR
AATTGGCACTGAGTTTCTCCTTCTTGCCATCATTTGCTTCATGAAATAATCTTTCTTTCGT
TTACATTTATAATCAAGTGCAGTAGAAAGATTTTAAATG Celera SNP ID: hCV8367043
Public SNP ID: rs1343151 SNP Chromosome Position: 67491717 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 807 SNP
Source: dbSNP; Celera; HapMap; ABI_Val; HGBASE Population (Allele,
Count): Caucasian (G,73|A,47) SNP Type: TRANSCRIPTION FACTOR
BINDING SITE; INTRON Context (SEQ ID NO: 287):
ATCTTGTTTCCAGAGTAGTGACATTTCTGTGCTCCTACCATCACCATGTAAGAATTCCCG
GGAGCTCCATGCCTTTTTAATTTTAGCCATTCTTCTGCCTM
ATTTCTTAAAATTAGAGAATTAAGGTCCCGAAGGTGGAACATGCTTCATGGTCACACAT
ACAGGCACAAAAACAGCATTATGTGGACGCCTCATGTATTT Celera SNP ID:
hCV11283764 Public SNP ID: rs10889677 SNP Chromosome Position:
67497708 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 6798 SNP Source: dbSNP; Celera; HapMap Population (Allele,
Count): Caucasian (C,87|A,33) SNP Type: UTR3 Context (SEQ ID NO:
288): GACCTTGAACTCCAGGGCTCAAATAATCTGCCCACCTTGGCCTCCCAAAGTGCTAGGAT
TACAGGCATGAGCCAATATGCCCAGCCAAATATCTTAATCAM
CATCATCATCATCATCATAAACTGCCGGTAGGAAGTTTGGCATAATGTGTCACATCAAT
TATAAATCACAGATGATTTTACTTGATATAGTTAGCTAGAG Celera SNP ID:
hCV26465573 Public SNP ID: rs11209030 SNP Chromosome Position:
67510363 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 19453 SNP Source: dbSNP; Celera; HapMap; ABI_Val
Population (Allele, Count): Caucasian (C,79|A,41) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 289):
CAGCCTAAATTTTAGGGCTTTATTATATAACATTCTCTTTTTAAATATGCGGTAGTTACG
GTCACCTTGGAAAGTTCTACAAAATATCCCTTAAGTTTTTY
GAACTTTCCCACATGGGAATCTTCTGGTTATGAGAGTTTGCTCTATTTAATATGTGTACG
GTTTCACTGCTAGGGTGGTTCTCCCACTTATCTTGAATCT Celera SNP ID: hCV30243123
Public SNP ID: rs6693831 SNP Chromosome Position: 67493455 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 2545 SNP
Source: dbSNP; HapMap Population (Allele, Count): Caucasian
(T,30|C,90) SNP Type: INTRON Context (SEQ ID NO: 290):
GGTTGAAGTATGGTCCACTGGGATTGGCCAAGACTCAGTTACTGTTACAGGCACATACT
CCTAAGTCAGGTTTTCACTCTTGTCTGCCTGTTAAGTTAGGW
TACAGTTCATCCACAGGGATTCAAATATAGAGGTATGAAGTCCTTCTCAGGCCATATTT
AGTTTGCTTTAACACTTGAATTCCACCCAAACAAATCAGCT Celera SNP ID:
hCV31222811 Public SNP ID: rs12085634 SNP Chromosome Position:
67491301 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 391 SNP Source: dbSNP Population (Allele, Count): no_pop
(A,-IT,-) SNP Type: INTRON Context (SEQ ID NO: 291):
AATTAGGCCTGCGAAAGAGACAGACTCCTTCCAGTGACAGAGTGTTAGGTGGCAAGTTC
AGAAGCTGTCAGTCTTGTTTTTCTCCATGTGGCCAGAATGAM
AGGAAGATGGCCCATAGACGCAGAATAAGAAGAATAATAAACAGATCCACAGAAAAG
GACAGAGGAGAGATGAAATGAGAACCCTGAATGCATTAGAATC Celera SNP ID:
hCV31222784 Public SNP ID: rs11209031 SNP Chromosome Position:
67512176 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 21266 SNP Source: dbSNP; HapMap Population (Allele,
Count): Caucasian (A,76|C,40) SNP Type: INTERGENIC; UNKNOWN Context
(SEQ ID NO: 292):
GAGGAGTTGCCATCTATTAATACTTATTTTCCACAAAATATTTTGGAAAGCCACTTCAAT
AGGATTTCACTCTTGGAAAAGTAGAGCTGTGTGGTCAAAAK
CAATATGAGAAAGCTGCCTTGCAATCTGAACTTGGGTTTTCCCTGCAATAGAAATTGAA
TTCTGCCTCTTTTTGAAAAAAATGTATTCACATACAAATCT Celera SNP ID:
hCV31222798 Public SNP ID: rs11465827 SNP Chromosome Position:
67497416 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 6506 SNP Source: dbSNP Population (Allele, Count):
Caucasian (T,117|G,3)
SNP Type: MICRORNA; UTR3 Context (SEQ ID NO: 293):
GGCCTCCCCAGCCATATGGAACTGTAAGTCCATTAAATCTCTTTTTTTTGCAAATTGCCC
AGTCTTGGGTATGTCTTTACCAGCAGCGTGAAAATGGACTW
ATACAGCATTTACCACAGTGTCTGGCTCATAGTAACTGTGGCAGAGCCTGCTAATTGTC
CGTTCAACTTCCGTTCTCAAATTCTTACTTCCTAACAGAAC Celera SNP ID:
hCV31222786 Public SNP ID: rs1857292 SNP Chromosome Position:
67510910 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 20000 SNP Source: dbSNP; HapMap; HGBASE Population
(Allele, Count): Caucasian (T,10|A,106) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 294):
TAGAAGTGGCTCTGTTTCAAGCTCTGGTAAGCCTATTAGCTAACTCTTTCCCCAACCTCA
TGTCATCTGAACAAAGGGTTTCTAGGCTAAAAATAAAATAM
TTTTTAAAAGTTCAAAAACAACTGGTCAACAGAATAGAGTCTGAGTTCTGTAACACAAG
ACTTCTGTGATCTGATCCACTCACCATTCCAGCTTTACTCC Celera SNP ID: hCV261079
Public SNP ID: rs10889676 SNP Chromosome Position: 67495155 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 4245 Related
Interrogated SNP: hCV11283764 (Power = .51) Related Interrogated
SNP: hCV1272302 (Power = .51) SNP Source: Celera; dbSNP Population
(Allele, Count): no_pop (A,-1C,-) SNP Type: INTRON Context (SEQ ID
NO: 295):
ACATTTTTTTTCAATTTCATGGAAAAGAGGTTTTTCATTTTTCCAAAAATTGTACCAAGG
TAAAGCAAAGTTCTAGTTGATGCAGGTGCATTGTATAGGCR
TTAGCAATACTGCCCTCATTATGCACTCATTAGACAGTAGTGCAACCCCAAGAAAAGGA
TGGTTAGATATTTCTTTATAGCAATGCAAGAACAGCCTAAC Celera SNP ID: hCV2720226
Public SNP ID: rs2863209 SNP Chromosome Position: 67505934 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 15024 Related
Interrogated SNP: hCV31222786 (Power = .51) SNP Source: dbSNP;
Celera; HGBASE Population (Allele, Count): Caucasian (G,12|A,106)
SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 296):
TTTATAAACAGCTAATCGGAACCTCTATTTGTCATAGGCTTTTGAGTTTATTGTTGGGAC
CCATAATAGGACCATTTTTTCTTTTTGTCTTCAAAATTATY
GTAGGCCAGGTGCAGTGGCTTACACCTGTAATCCCAGCACTTCGGGAGGCTGAGGCGG
GTGGATCAAGTGAGGTCAGGAGTTCAAAACCAGCCTGGCCAA Celera SNP ID:
hCV2720231 Public SNP ID: rs11209034 SNP Chromosome Position:
67517272 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 26362 Related Interrogated SNP: hCV2720238 (Power = .51)
SNP Source: dbSNP; Celera Population (Allele, Count): Caucasian
(T,37|C,83) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 297):
AGCCAGTTAATGTCTTTAACAATAAGTGTTAAGGAGCAGCTGCTGCACTTGGATAACAA
GTAATTCAAGGCGCCCACTTAACAGAAATGTTAAACTATAAS
AAGAACCATCTGAGGATTAACAGAAACTTTTTTTTTGTAGATTTCAAGGGAACTTGCCTT
TCAGAATAATAGTACCTAAAGTATTTATAAACAGCTAATC Celera SNP ID: hCV2720233
Public SNP ID: rs11209033 SNP Chromosome Position: 67517088 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 26178 Related
Interrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP;
Celera; HapMap; ABI_Val Population (Allele, Count): Caucasian
(C,83|G,37) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 298):
ATTGAAAAGAAGCAGAGCAATAGAGATGAGAGGAAAATCTGAAAAGATAATGACACA
ATTTCCCACTTAATTTTCATTAAGTAAGAGATGAAAACTTTAGM
CTCGGCATCAGGAAGTTTGATTTCTTTAATTAATTTTTTTTTTGAGTCAGGGTCTCACTCT
GTTGCCCAGAGTGAGTGCAGTGGCATGGTCACAGCTCAC Celera SNP ID: hCV2720251
Public SNP ID: rs11465817 SNP Chromosome Position: 67493685 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 2775 Related
Interrogated SNP: hCV11283764 (Power = .51) SNP Source: dbSNP;
Celera; HapMap Population (Allele, Count): Caucasian (C,66|A,42)
SNP Type: INTRON Context (SEQ ID NO: 299):
AGTCCTGGAAAAACAAGACAGCCTCAGCTCAGTAGTTCCCATACAAATTCCAATGTTTA
GATTGTTTGGCATAACTGGAGTCACATGCTTATCCATGAACY
AAATAATCATCGTTGACAGGAAATATGGTATTCTCATTGGCCAGGTCAAGTCACATGCT
CACCAGAGGGGTGATGGGGAACTAGCTCCACTCTTGCGCGT Celera SNP ID: hCV3277187
Public SNP ID: rs7546245 SNP Chromosome Position: 67523062 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 32152 Related
Interrogated SNP: hCV2720238 (Power = .51) SNP Source: dbSNP;
Celera Population (Allele, Count): Caucasian (T,84|C,36) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 300):
GAATGGCCTAGGAAAGTTACATTCCAGAAGGAAACATGTTATTACACATAGGAATCGA
TTGGTCCTCCATGAGTACCTACAATTGAATTCTATGTATTAAM
ACCGCAGAAAAACACATACAGATAGAAAATATTTTTAATCAAGGACTAGTATCCAAAG
CAAAACAAAGTGGAAATTTGGTAATTATCCTGTGAATTTCTG Celera SNP ID:
hCV3277191 Public SNP ID: rs12119179 SNP Chromosome Position:
67520003 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 29093 Related Interrogated SNP: hCV2720238 (Power = .51)
SNP Source: dbSNP; Celera Population (Allele, Count): Caucasian
(A,83|C,37) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 301):
AACGACTCTTGGTGTCTTCCAGCGCTAATGATTTATAATTAAGTTAGATTTGTAACCTTA
AAATACTTTATAGCATTTACCCTGCTTGTGAGTGTGTATAS
ATTTAACAGAATTCAACAAGCACGTGCTGAGAAAATTCTTTACCCAGGGCATTCAGCTA
CCTACAGTATAGTCAGAGGGAAATAAAACATGGTTTGGAAT Celera SNP ID: hCV3277193
Public SNP ID: rs12141431 SNP Chromosome Position: 67519611 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 28701 SNP
Source: dbSNP; Celera Population (Allele, Count): Caucasian
(G,84|C,36) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO: 302):
GCTCATGCTTATGAAATTCACTGGTCTTACCATGTTCCCCATCATCCTGAAGAAGCTGGA
TTGATATAATGGTGGAATGGCCTATTGAAGTCACAATTACW
GTGCCAACTAGATGACAATACTTTGCAGGGCTGGGACAAAGTTCTCCAGAAGGCCGGG
TATGCTCTGAATCAGTGTCCAATATGTTACTGTTTCTCCCAA Celera SNP ID:
hCV11283811 Public SNP ID: rs4655536 SNP Chromosome Position:
67530442 SNP in Genomic Sequence: SEQ ID NO: 19 SNP Position
Genomic: 39532 Related Interrogated SNP: hCV31222786 (Power = .51)
SNP Source: dbSNP; Celera Population (Allele, Count): Caucasian
(T,108|A,12) SNP Type: INTERGENIC; UNKNOWN Context (SEQ ID NO:
303): GTAATCTATCACACATGAAAAAAGCTTTTATCAAGCTTAAAGGATTACAGCATTGTTTG
ATCTTCTGCAAATGTTTCCACTGCAGCGAGTGCCTCCTTTTY
GCCCCCTAGAGTGGGAAGGAAGCTGCTTTCTCATTCTGTGGTGTCTTAACCCACATCACT
ATTCAGCACAAAGGAGACACTTCTGATTCTGTCTTTGCCA Celera SNP ID: hCV11728628
Public SNP ID: rs2000252
SNP Chromosome Position: 67500143 SNP in Genomic Sequence: SEQ ID
NO: 19 SNP Position Genomic: 9233 Related Interrogated SNP:
hCV8367042 (Power = .51) SNP Source: Celera; HGBASE; HapMap; dbSNP
Population (Allele, Count): no_pop (C,-IT,-) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 304):
ACTGCAAATCATCTAAGAAGAGAAAAACCCCTCTGAATTACATGACTGAGTTTCAGAAT
GTGAGTAAAGTATGGCTAACCAAAATGTTCAAGCAAACTGAW
GCAAATTTCCTTTTCTATGACTGTGTAAGCAAAACTCTTTTGCACGATACTAAGTTTGAT
GTGGTGTAGCATGTAAAAGAGAAAGCACCTTTATCTGTGT Celera SNP ID: hCV29129920
Public SNP ID: rs6677188 SNP Chromosome Position: 67512991 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 22081 Related
Interrogated SNP: hCV26465573 (Power = .51) Related Interrogated
SNP: hCV31222784 (Power = .51) SNP Source: dbSNP Population
(Allele, Count): Caucasian (T,80|A,40) SNP Type: INTERGENIC;
UNKNOWN Context (SEQ ID NO: 305):
TTTGCAATTCTAGAATCGGACAACACCTCATACTATAAAACAGAGTGAGTGTTCTGATG
AGCTGAGCAGAGGAGGTTGATTTAAGGAACTTTCTTATCACR
CTGGCGAAAACTGGCCTGTTTAGGGATTTGGCTGTTATCTCTGTGTCCTGATTTGTTGAA
AGGTCAGATAAAGATCTTAGTTTCAGCAGGTTAGTGTGGA Celera SNP ID: hCV30423493
Public SNP ID: rs7539328 SNP Chromosome Position: 67505191 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 14281 Related
Interrogated SNP: hCV31222784 (Power = .51) SNP Source: dbSNP;
HapMap Population (Allele, Count): Caucasian (G,76|A,42) SNP Type:
INTERGENIC; UNKNOWN Context (SEQ ID NO: 306):
TCTCTTTTTTTTGCAAATTGCCCAGTCTTGGGTATGTCTTTACCAGCAGCGTGAAAATGG
ACTTATACAGCATTTACCACAGTGTCTGGCTCATAGTAACW
GTGGCAGAGCCTGCTAATTGTCCGTTCAACTTCCGTTCTCAAATTCTTACTTCCTAACAG
AACCCCTATGTCATTGATGATAGCAGTTCTCTCAGTGAAA Celera SNP ID: hCV31222785
Public SNP ID: rs12045232 SNP Chromosome Position: 67510947 SNP in
Genomic Sequence: SEQ ID NO: 19 SNP Position Genomic: 20037 Related
Interrogated SNP: hCV26465573 (Power = .51) Related Interrogated
SNP: hCV31222784 (Power = .51) SNP Source: dbSNP; HapMap Population
(Allele, Count): Caucasian (T,80|A,40) SNP Type: INTERGENIC;
UNKNOWN Gene Number: 8 Gene Symbol: Chr5:158452593..158472593 Gene
Name: Chromosome: 5 OMIM NUMBER: OMIM Information: Genomic Sequence
(SEQ ID NO: 20): SNP Information Context (SEQ ID NO: 307):
ATTTCCTTTGGCTGTGCAGAGGCAGCACATACCTCACCTGGGGTGGTGAGTGTGCTTTAT
TTTAATCAAGCCGAGTGTATTCATAGCTTTTCTTCTTGGTR
TCCTTGTGCTTTCAGTCTGGCTTTCTCATCCTGTAATAAATGTTTAAGTAGGAAGGAGGC
TAAAGAGAAGGTGGAAGAGAGACAGAGTGAGTGACAGAAA Celera SNP ID: hCV1992722
Public SNP ID: rs7732511 SNP Chromosome Position: 158462593 SNP in
Genomic Sequence: SEQ ID NO: 20 SNP Position Genomic: 10000 SNP
Source: dbSNP; Celera; HapMap Population (Allele, Count): Caucasian
(G,101|A,19) SNP Type: INTRON
TABLE-US-00003 TABLE 3 Primer 1 Primer 2 Marker Alleles
(Allele-Specific Primer) (Allele-Specific Primer) Common Primer
hCV11264637 A/G CCAAAACCAGACAAGGACAT CCAAAACCAGACAAGGACAC
GCTGCAATGCCTGGTGAGTATTAT (SEQ ID NO: 308) (SEQ ID NO: 309) (SEQ ID
NO: 310) hCV11269323 A/G GGGTTGTCCATGACCTCTA GGTTGTCCATGACCTCTG
CCACTGAGCGGGTAAACACTTAG (SEQ ID NO: 311) (SEQ ID NO: 312) (SEQ ID
NO: 313) hCV11283754 A/G GGGCACTCTGAATTATCAATCAAT
GGCACTCTGAATTATCAATCAATTG TCAAGGTGTAGGTAGGTCTGTGTA TA (SEQ ID NO:
314) (SEQ ID NO: 315) (SEQ ID NO: 316) hCV11283764 A/C
AATTTTAGCCATTCTTCTGCCTA TTTTAGCCATTCTTCTGCCTC
AAATACATGAGGCGTCCACATAATG (SEQ ID NO: 317) (SEQ ID NO: 318) C (SEQ
ID NO: 319) hCV11314640 C/T GGCCCTGACTGATTTCATG
TGGCCCTGACTGATTTCATA GGTGGCCTCAGCTTCCTT (SEQ ID NO: 320) (SEQ ID
NO: 321) (SEQ ID NO: 322) hCV1272298 A/G TGCAAAAACCTACCCAGTTT
TGCAAAAACCTACCCAGTTC TTCATTAGACAACAGAGGAGACAT (SEQ ID NO: 323) (SEQ
ID NO: 324) (SEQ ID NO: 325) hCV1272302 A/G
TAATAGGAAACTAATATAGAAGAT TAGGAAACTAATATAGAAGATGATGA
ATGTTTGCCAAGTTGGTCTTGAACT GATGACT (SEQ ID NO: 326) CC (SEQ ID NO:
327) (SEQ ID NO: 328) hCV15803290 A/G CTCTCCCTGGGGATGAA
CTCTCCCTGGGGATGAG CAATTGACTGTAACTGCTCCAAGAC (SEQ ID NO: 329) (SEQ
ID NO: 330) A (SEQ ID NO: 331) hCV15894459 A/G ATTGCCTTTCCCAACAAGT
TGCCTTTCCCAACAAGC AATTTTGGTCCCACCGCTCATT (SEQ ID NO: 332) (SEQ ID
NO: 333) (SEQ ID NO: 334) hCV1992693 A/G CGGCCATGGTTCTAAGAAA
CGGCCATGGTTCTAAGAAG GAAATGTGGGCTGAGGGATAG (SEQ ID NO: 335) (SEQ ID
NO: 336) (SEQ ID NO: 337) hCV1994965 A/G TTACTTCCTACATTTACAACCTAG
ACTTCCTACATTTACAACCTAGAAC GAGGAGACCTCAAAGCAGAACCTT AAT (SEQ ID NO:
338) (SEQ ID NO: 339) A (SEQ ID NO: 340) hCV1994966 C/T
CTCCTTAAGAAGAGAGATCAACA CTCCTTAAGAAGAGAGATCAACAAA
TGGTCTCAATCTCCTGACCTTGTG AG (SEQ ID NO: 341) (SEQ ID NO: 342) (SEQ
ID NO: 343) hCV1994967 C/G CTGGGAATCAGATGATTGAGC
CTGGGAATCAGATGATTGAGG GTGTAAATCTGCCAATTAGCCATCT (SEQ ID NO: 344)
(SEQ ID NO: 345) CT (SEQ ID NO: 346) hCV1994973 A/G
GCTCTACCTTTATGCACTGTTTTA CTCTACCTTTATGCACTGTTTTG
GTCACAATGAAATACTAGTCAGGAC (SEQ ID NO: 347) (SEQ ID NO: 348) TCTCA
(SEQ ID NO: 349) hCV1994974 C/T GCAGTGGAGTTATTAGAAGTTATT
GCAGTGGAGTTATTAGAAGTTATTTA GTGCCCTGTGGGGTTAAACA TAGATG (SEQ ID NO:
350) GATA (SEQ ID NO: 351) (SEQ ID NO: 352) hCV1994990 C/G
GATGCAACTTTAGAGGCATTTG GATGCAACTTTAGAGGCATTTC
TTAGGACTGGAAACCACGAAGTCA (SEQ ID NO: 353) (SEQ ID NO: 354) A (SEQ
ID NO: 355) hCV1994992 C/G GATCAAAGATGTAAATCCAGACTA
GATCAAAGATGTAAATCCAGACTATT CCTCTGTGTTCACACTGATATCAAT TTG (SEQ ID
NO: 356) C (SEQ ID NO: 357) ACCT (SEQ ID NO: 358) hCV1995017 C/T
TGGCAGCCTCATAATATTTCAAC TGGCAGCCTCATAATATTTCAAT
CAAAGGAACTCCTCTTGTGACATCT (SEQ ID NO: 359) (SEQ ID NO: 360) (SEQ ID
NO: 361) hCV2081970 C/T AATTAACTTTAGAATCAGACTTGA
AAATTAACTTTAGAATCAGACTTGAT CAGCCCAGGAGTTGGACAAG TACAG (SEQ ID NO:
362) ACAA (SEQ ID NO: 363) (SEQ ID NO: 364) hCV2081982 A/G
TTCGATCAGGCAGTAGGATAT TCGATCAGGCAGTAGGATAC
CATTTTGTTGGTTACTAACAGCACT (SEQ ID NO: 365) (SEQ ID NO: 366) GAA
(SEQ ID NO: 367) hCV2084270 A/G CAACCAAGAAATAGTCATTTACAG
CAACCAAGAAATAGTCATTTACAGAG ATCAGGAGCTGGAGGAAACTTCT AA (SEQ ID NO:
368) (SEQ ID NO: 369) (SEQ ID NO: 370) hCV2084281 C/T
GGGGTGCTGTGTTTCTTTC GGGGTGCTGTGTTTCTTTT CTAACAGCTGTAATGAGGTATAGTT
(SEQ ID NO: 371) (SEQ ID NO: 372) CACATACTC (SEQ ID NO: 373)
hCV2084293 G/T CAATGAGCATTTAGCATCG TTCAATGAGCATTTAGCATCT
TGGAGGAAAAGTGGAAGATATTA (SEQ ID NO: 374) (SEQ ID NO: 375) (SEQ ID
NO: 376) hCV2084294 C/T ATTTTCATCCTGGATCAGAAC ATTTTCATCCTGGATCAGAAT
AGTTGCCCAGGATCATATGT (SEQ ID NO: 377) (SEQ ID NO: 378) (SEQ ID NO:
379) hCV2084295 C/T GCTAAAGACTTGCTAAGAGTTTG
TGCTAAAGACTTGCTAAGAGTTTA TGTGTAACTTCAGGAAAATGTCTTA (SEQ ID NO: 380)
(SEQ ID NO: 381) (SEQ ID NO: 382) hCV2084296 C/T GGAATTCTGCTGTAAGGC
AAGGAATTCTGCTGTAAGGT CTCCTGGCTGTTCCAGATAT (SEQ ID NO: 383) (SEQ ID
NO: 384) (SEQ ID NO: 385) hCV2084297 A/C ACTAGGAACTCTCTCCCCAAT
CTAGGAACTCTCTCCCCAAG TGTTGTCCCCTCTGACTCTC (SEQ ID NO: 386) (SEQ ID
NO: 387) (SEQ ID NO: 388) hCV2084298 G/T GCACCAAAGAAAGGGATAAAC
GCACCAAAGAAAGGGATAAAA CCTCATCGAGTTTTGGAGTCT (SEQ ID NO: 389) (SEQ
ID NO: 390) (SEQ ID NO: 391) hCV2084301 C/T
CACAGTAAATTCGGTGTTAGTTAT CACAGTAAATTCGGTGTTAGTTATT
TCCACTGGTGATTTAAAACAGA C (SEQ ID NO: 392) (SEQ ID NO: 393) (SEQ ID
NO: 394) hCV261080 A/C CAAGCTATGTGTGTTCCTGATAAA
AAGCTATGTGTGTTCCTGATAAC CACATGTTTGGGCTCATTTCTATCA (SEQ ID NO: 395)
(SEQ ID NO: 396) (SEQ ID NO: 397) hCV26465573 A/C
GCCCAGCCAAATATCTTAATCAA GCCCAGCCAAATATCTTAATCAC
CCCCTGTGGATTATCTCTAGCTAAC (SEQ ID NO: 398) (SEQ ID NO: 399) T (SEQ
ID NO: 400) hCV27106358 A/C GGTGGGGTCAACATTACTAAA
GGTGGGGTCAACATTACTAAC GCTGAGGCCACCCAAACTAAATA (SEQ ID NO: 401) (SEQ
ID NO: 402) (SEQ ID NO: 403) hCV27106365 G/T
GAGAATGAGATAAGCCTCAAGAG AGAGAATGAGATAAGCCTCAAGAT
CATAGAGAGTCTTTGTGCTCTGGTT (SEQ ID NO: 404) (SEQ ID NO: 405) GTA
(SEQ ID NO: 406) hCV27106385 A/G TCACACTGTCAGACACATCT
CACACTGTCAGACACATCC AAGGGGCTTCTTGAGAGGAAATGA (SEQ ID NO: 407) (SEQ
ID NO:408) (SEQ ID NO: 409) hCV2720238 A/G CTACATCACCCTCTTTGCAATA
ACATCACCCTCTTTGCAATG CGGTGGTTCTTCACAGGTTTCTAAT (SEQ ID NO: 410)
(SEQ ID NO: 411) A (SEQ ID NO: 412) hCV2720250 C/T
TTTATCACAATGCAAACTTCGC CTTTATCACAATGCAAACTTCGT
CTGCAGGGATTGACTGGTTTTGTTA (SEQ ID NO: 413) (SEQ ID NO: 414) (SEQ ID
NO: 415) hCV2720255 G/T AGCTTTTGCAAGCTCAAAATTAC
AGCTTTTGCAAGCTCAAAATTAA CAGGCCACCACTGTGAAAGTAA (SEQ ID NO: 416)
(SEQ ID NO: 417) (SEQ ID NO: 418) hCV27467945 A/G
AGTGCTTTTGCGACATGAT GTGCTTTTGCGACATGAC AGGACAGTCCTGGAGACTATCTTTA
(SEQ ID NO: 419) (SEQ ID NO: 420) AAGA (SEQ ID NO: 421) hCV27471935
C/G GCTTTGTCAGAACTGCTACTAAC GCTTTGTCAGAACTGCTACTAAG
CAGTGTCCAAGAAGGCTTGACTT (SEQ ID NO: 422) (SEQ ID NO: 423) (SEQ ID
NO: 424) hCV27508808 A/C ACAACAGACGGCTGAGTA CAACAGACGGCTGAGTC
AGTGGTTCTCAAGGTGTGGTCTTA (SEQ ID NO: 425) (SEQ ID NO: 426) (SEQ ID
NO: 427) hCV27936085 C/T GCTGTTGTCCTCATTATACAAATG
GCTGTTGTCCTCATTATACAAATGA CTCCCGTTAATTCCCAAAGTGTTAC G (SEQ ID NO:
428) (SEQ ID NO: 429) TT (SEQ ID NO: 430) hCV27952715 A/G
TGGGCAATCATATCCACTCT GCCCTTTGCCAAGCGATACT GGGCAATCATATCCACTCC (SEQ
ID ID NO: 431) (SEQ ID NO:432) (SEQ ID NO: 433) hCV28024675 C/T
GCTGACTGAACCACAGG GAAGTGGGCGGCAGAGAA AGCTGACTGAACCACAGA (SEQ ID NO:
434) (SEQ ID NO: 435) (SEQ ID NO: 436) hCV29349404 A/C
AGTCTATGTTATCAGGCCACTAAT GTCTATGTTATCAGGCCACTAAG
GATGCTGTGGTCTGAACGTTTATGT (SEQ ID NO: 437) (SEQ ID NO:438) (SEQ ID
NO: 439) hCV29349406 G/T CTTCCTCATGCCCAAAGG TCTTCCTCATGCCCAAAGT
GAGGTGACAGCGATTAGGGAGTAG (SEQ ID NO: 440) (SEQ ID NO: 441) (SEQ ID
NO: 442) hCV29619986 C/T GCCCTTCTCAGTGAATCTCG GCCCTTCTCAGTGAATCTCA
CTGGTGGACAGACACAACCTAAAC (SEQ ID NO: 443) (SEQ ID NO: 444) (SEQ ID
NO: 445) hCV2989999 A/C TGATAAGAGGCAGAGTTTAATTCA
TGATAAGAGGCAGAGTTTAATTCAC CACACACCCTTGGGCATTAATTAGT A (SEQ ID NO:
446) (SEQ ID NO: 447) (SEQ ID NO: 448) hCV2990018 C/T
CAGCCTTGGAGTTCACC GCAGCCTTGGAGTTCACT TGTGCTCAGCAGAAAAGATATAT (SEQ
ID NO: 449) (SEQ ID NO: 450) (SEQ ID NO: 451) hCV29927086 C/T
CAGGGTGTCGAGAACAAC TCAGGGTGTCGAGAACAAT CTCAGTCAAATGTAAGGCAGATACT
(SEQ ID NO: 452) (SEQ ID NO: 453) GT (SEQ ID NO: 454) hCV30243123
C/T CCCATGTGGGAAAGTTCG TCCCATGTGGGAAAGTTCA
CTCAGAACAGCCTAAATTTTAGGGC (SEQ ID NO: 455) (SEQ ID NO: 456) TTTAT
(SEQ ID NO: 457) hCV30279129 C/T GCGCTAATTACACTACCAAATG
GTAGCGCTAATTACACTACCAAATA GAACTCTATAACTGCCTAGCAAGAT (SEQ ID NO:
458) (SEQ ID NO: 459) TATGC (SEQ ID NO: 460) hCV30377542 G/T
CAATGGCAAAGCTGTTAGTG ACAATGGCAAAGCTGTTAGTT
GCTGGGATTATAGGTGTGCACTACT (SEQ ID NO: 461) (SEQ ID NO: 462) (SEQ ID
NO: 463) hCV30449508 A/C ACTGCTTCTAGCCCAGTT ACTGCTTCTAGCCCAGTG
ACCTAAGGCAAGCCATCTGATACA (SEQ ID NO: 464) (SEQ ID NO: 465) (SEQ ID
NO: 466) hCV30611467 C/T TCTACCAATCAATAAGGTAAGACA
CTTCTACCAATCAATAAGGTAAGACA GCCAGGCACCTTCTCAGTCTAT G (SEQ ID NO:
467) A (SEQ ID NO: 468) (SEQ ID NO: 469) hCV31222784 A/C
TCCATGTGGCCAGAATGAA CCATGTGGCCAGAATGAC GCATTCAGGGTTCTCATTTCATCTC
(SEQ ID NO: 470) (SEQ ID NO: 471) T (SEQ ID NO: 472) hCV31222786
A/T ACACTGTGGTAAATGCTGTATT GACACTGTGGTAAATGCTGTATA
CCCAGCCATATGGAACTGTAAGT (SEQ ID NO: 473) (SEQ ID NO: 474) (SEQ ID
NO: 475) hCV31222798 G/T AGGCAGCTTTCTCATATTGC
CAAGGCAGCTTTCTCATATTGA ATCGTGAATGAGGAGTTGCCATCTA (SEQ ID NO: 476)
(SEQ ID NO: 477) (SEQ ID NO: 478) hCV31222811 A/T
TCCCTGTGGATGAACTGTAT TCCCTGTGGATGAACTGTAA GATTGGCCAAGACTCAGTTACTGTT
(SEQ ID NO: 479) (SEQ ID NO: 480 (SEQ ID NO: 481) hCV31222825 A/G
GGGAAGCAAAATTAACCTTTACT GGGAAGCAAAATTAACCTTTACC
CACATTTGCCAGAGATGCACTTCTA (SEQ ID NO: 482) (SEQ ID NO: 483) (SEQ ID
NO: 484) hCV31222826 C/T TGAAGCTCACCACTAAGAATTTAT
TGAAGCTCACCACTAAGAATTTATAT CACAACTACCCCAGGAAACAACT AC (SEQ ID NO:
485) (SEQ ID NO: 486) (SEQ ID NO: 487) hCV31222838 G/T
GATGGGTTAAAATGGGCAATTC TGATGGGTTAAAATGGGCAATTA
GCTAACAGTTGCTTCCATCTCTACA (SEQ ID NO: 488) (SEQ ID NO: 489) (SEQ ID
NO: 490)
hCV3169817 A/G TGTATGAAGTGCTGAGGATAAATA TGTATGAAGTGCTGAGGATAAATAG
ATTTCCCCCACCAACACACATAC A (SEQ ID NO: 491) (SEQ ID NO: 492) (SEQ ID
NO: 493) hCV31985582 A/G CTAATAAATAATGAATATGCTGCA
ATAAATAATGAATATGCTGCACCG GCTTCCAGCTCCATCCAAGTTG CCA (SEQ ID NO:
494) (SEQ ID NO: 495) (SEQ ID NO: 496) hCV31985592 C/T
TCACCAGGTCACTGCC TTCACCAGGTCACTGCT GCAGTTTTCTGCCTCCAGGAAATAC (SEQ
ID NO: 497) (SEQ ID NO: 498) (SEQ ID NO: 99) hCV31985602 G/T
TTTTTGCGGCAGATGAC TTTTTGCGGCAGATGAA GGCTTGTTTTGGGAGAGTATG (SEQ ID
NO: 500) (SEQ ID NO: 501) (SEQ ID NO:502) hCV3220380 C/T
GATGGTCACAGTTATGATTCCC GATGGTCACAGTTATGATTCCT
CCTGGGTGACAGAATGAGACTC (SEQ ID NO: 503) (SEQ ID NO: 504) (SEQ ID
NO: 505) hCV3220386 C/T CTCCCACGGCTTGTAATC CTCCCACGGCTTGTAATT
GCACATTTAGCCAATTTCAACACAT (SEQ ID NO: 506) (SEQ IDNO: 507) AT (SEQ
ID NO: 508) hCV7537756 C/G TGGAGCTCAAATGTTGGTTAG
TGGAGCTCAAATGTTGGTTAC CCTGTTCTTGCAAGGAGGTGATC (SEQ ID NO: 509) (SEQ
ID NO: 510) (SEQ ID NO: 511) hCV7537839 G/T CATCTGTCTGCTTCTCACAG
CATCTGTCTGCTTCTCACAT GTCTGGAAGGCAAAAAGATC (SEQ ID NO: 512) (SEQ ID
NO: 513) (SEQ ID NO: 514) hCV7537857 A/C GGCCAGTCCTCACACAT
GGCCAGTCCTCACACAG AAGACTCCCAAGGATAGCGTGTTA (SEQ ID NO: 515) (SEQ ID
NO: 516) G (SEQ ID NO: 517) hCV7538743 C/G TGGACATTTTGTTGTGTTTGC
TTGGACATTTTGTTGTGTTTGG CCACCCATATCACATGTCATCAGT (SEQ ID NO: 518)
(SEQ ID NO: 519) (SEQ ID NO: 520) hCV7538755 C/G
TTAGTCATTTAAAGTCAGGTTAAT TAGTCATTTAAAGTCAGGTTAATG CGGTGTGGCCTTGTGAG
GTTC (SEQ ID NO: 521) TTG (SEQ ID NO: 522) (SEQ ID NO:523)
hCV7538761 C/T GTGTACCAAATTCATTGCTCTAAT GTGTACCAAATTCATTGCTCTAATT
CAAAGCTTCTTGATGCCTTGTTT C (SEQ ID NO: 524) (SEQ ID NO: 525) (SEQ ID
NO: 526) hCV8367042 C/G GGCACACACCACCATTTC GGCACACACCACCATTTG
GGCAAAGACAGGCAGATCACT (SEQ ID NO: 527) (SEQ ID NO: 528) (SEQ ID NO:
529) hCV8367043 A/G GGAGAAACTCAGTGCCAATTT GGAGAAACTCAGTGCCAATTC
CATTGAGTATTTCTAAGCTGCTCGA (SEQ ID NO: 530) (SEQ ID NO: 531) TAGA
(SEQ ID NO: 532) hDV70267720 C/T GGAATGTCATCCAGCCATAAAG
GGAATGTCATCCAGCCATAAAA GCCTTTCGTGTGGGTTCTTTAACT (SEQ ID NO: 533)
(SEQ ID NO: 534) (SEQ ID NO: 535) hDV71045748 A/G
AACTGACGACCAAGACCA ACTGACGACCAAGACCG TGAGTGGTGCCTGCCTTACTATT (SEQ
ID NO: 536) (SEQ ID NO: 537) (SEQ ID NO: 538) hDV79877074 C/T
CTGTCTCCGAGAGAGGG TCTCCGAGAGAGGCTCTAA GGGCTGATGCTTGGAGATTGT (SEQ ID
NO: 539) (SEQ ID NO: 540) (SEQ ID NO: 541)
TABLE-US-00004 TABLE 4 Interrogated SNP Interrogated rs LD SNP LD
SNP rs Power Threshold r.sup.2 r.sup.2 hCV11283764 rs10889677
hCV1272302 rs2201841 0.51 0.9 0.9325 hCV11283764 rs10889677
hCV261079 rs10889676 0.51 0.9 1 hCV11283764 rs10889677 hCV2720251
rs11465817 0.51 0.9 0.9095 hCV11314640 rs1833754 hCV27106364
rs4262088 0.51 0.9 1 hCV11314640 rs1833754 hCV7538744 rs1422880
0.51 0.9 1 hCV11314640 rs1833754 hCV7538751 rs1422879 0.51 0.9 1
hCV11314640 rs1833754 hCV7538752 rs1363669 0.51 0.9 1 hCV11314640
rs1833754 hDV70836316 rs17056705 0.51 0.9 1 hCV1272302 rs2201841
hCV11283764 rs10889677 0.51 0.9 0.9325 hCV1272302 rs2201841
hCV261079 rs10889676 0.51 0.9 0.9325 hCV15894459 rs2546892
hCV15824051 rs2853697 0.51 0.9 0.9345 hCV15894459 rs2546892
hCV27467946 rs3181226 0.51 0.9 0.9345 hCV1994965 rs953861
hCV1994960 rs4921483 0.51 0.9 1 hCV1994965 rs953861 hCV1994973
rs1157509 0.51 0.9 1 hCV1994965 rs953861 hCV1994974 rs1157510 0.51
0.9 1 hCV1994965 rs953861 hCV1994986 rs11749573 0.51 0.9 1
hCV1994965 rs953861 hCV30017148 rs9313808 0.51 0.9 1 hCV1994965
rs953861 hCV7538743 rs1363670 0.51 0.9 1 hCV1994990 rs6861600
hCV11264637 rs6864071 0.51 0.9 0.9596 hCV1994990 rs6861600
hCV11269323 rs11135059 0.51 0.9 0.9596 hCV1994990 rs6861600
hCV1994971 rs7725339 0.51 0.9 0.9547 hCV1994990 rs6861600
hCV27106359 rs12522665 0.51 0.9 1 hCV1994990 rs6861600 hCV27106365
rs4379175 0.51 0.9 0.9564 hCV1994990 rs6861600 hCV29349404
rs7704367 0.51 0.9 1 hCV1994990 rs6861600 hCV31985582 rs6556412
0.51 0.9 0.9568 hCV2084270 rs2082412 hCV15803290 rs2421047 0.51 0.9
1 hCV2084270 rs2082412 hCV15879826 rs2288831 0.51 0.9 1 hCV2084270
rs2082412 hCV2084281 rs7730390 0.51 0.9 1 hCV2084270 rs2082412
hCV2084293 rs3212227 0.51 0.9 0.9699 hCV2084270 rs2082412
hCV27471935 rs3212217 0.51 0.9 0.9699 hCV2084270 rs2082412
hCV27486507 rs3212219 0.51 0.9 0.9699 hCV2084270 rs2082412
hCV27508808 rs3212218 0.51 0.9 1 hCV2084270 rs2082412 hCV27883435
rs4921442 0.51 0.9 0.9451 hCV2084270 rs2082412 hCV29349409
rs6859018 0.51 0.9 0.9699 hCV2084270 rs2082412 hCV29619986
rs10072923 0.51 0.9 1 hCV2084270 rs2082412 hCV29927086 rs3213094
0.51 0.9 0.9699 hCV2084270 rs2082412 hCV30449508 rs3212220 0.51 0.9
1 hCV2084270 rs2082412 hCV30557642 rs10056599 0.51 0.9 1 hCV2084270
rs2082412 hDV71045748 rs6894567 0.51 0.9 0.9476 hCV2084270
rs2082412 hDV75439995 rs3213097 0.51 0.9 1 hCV2084281 rs7730390
hCV15803290 rs2421047 0.51 0.9 0.9061 hCV2084281 rs7730390
hCV2084270 rs2082412 0.51 0.9 1 hCV2084281 rs7730390 hCV2084293
rs3212227 0.51 0.9 1 hCV2084281 rs7730390 hCV27471935 rs3212217
0.51 0.9 1 hCV2084281 rs7730390 hCV27486507 rs3212219 0.51 0.9 1
hCV2084281 rs7730390 hCV27508808 rs3212218 0.51 0.9 1 hCV2084281
rs7730390 hCV29349409 rs6859018 0.51 0.9 1 hCV2084281 rs7730390
hCV29619986 rs10072923 0.51 0.9 0.9061 hCV2084281 rs7730390
hCV29927086 rs3213094 0.51 0.9 1 hCV2084281 rs7730390 hCV30449508
rs3212220 0.51 0.9 0.9061 hCV2084281 rs7730390 hCV30557642
rs10056599 0.51 0.9 1 hCV2084281 rs7730390 hDV75439995 rs3213097
0.51 0.9 0.905 hCV2084293 rs3212227 hCV15803290 rs2421047 0.51 0.9
1 hCV2084293 rs3212227 hCV15879826 rs2288831 0.51 0.9 1 hCV2084293
rs3212227 hCV2084270 rs2082412 0.51 0.9 0.9699 hCV2084293 rs3212227
hCV2084281 rs7730390 0.51 0.9 1 hCV2084293 rs3212227 hCV27471935
rs3212217 0.51 0.9 1 hCV2084293 rs3212227 hCV27486507 rs3212219
0.51 0.9 1 hCV2084293 rs3212227 hCV27508808 rs3212218 0.51 0.9 1
hCV2084293 rs3212227 hCV27883435 rs4921442 0.51 0.9 0.9451
hCV2084293 rs3212227 hCV29349409 rs6859018 0.51 0.9 1 hCV2084293
rs3212227 hCV29619986 rs10072923 0.51 0.9 1 hCV2084293 rs3212227
hCV29927086 rs3213094 0.51 0.9 1 hCV2084293 rs3212227 hCV30449508
rs3212220 0.51 0.9 1 hCV2084293 rs3212227 hCV30557642 rs10056599
0.51 0.9 0.9699 hCV2084293 rs3212227 hDV71045748 rs6894567 0.51 0.9
0.9476 hCV2084293 rs3212227 hDV75439995 rs3213097 0.51 0.9 1
hCV2084294 rs3213120 hCV31985602 rs3213119 0.51 0.9 1 hCV2084296
rs2853696 hCV11316602 rs1865014 0.51 0.9 1 hCV2084296 rs2853696
hCV2084251 rs10515780 0.51 0.9 1 hCV2084296 rs2853696 hCV2084252
rs10866711 0.51 0.9 1 hCV2084296 rs2853696 hCV2084259 rs7708700
0.51 0.9 1 hCV2084296 rs2853696 hCV2084263 rs10515782 0.51 0.9 1
hCV2084296 rs2853696 hCV2084265 rs7736656 0.51 0.9 1 hCV2084296
rs2853696 hCV2084266 rs10042630 0.51 0.9 0.9704 hCV2084296
rs2853696 hCV2084274 rs1433047 0.51 0.9 1 hCV2084296 rs2853696
hCV2084277 rs6874870 0.51 0.9 1 hCV2084296 rs2853696 hCV27936085
rs4921437 0.51 0.9 0.9421 hCV2084296 rs2853696 hCV30629526
rs4921458 0.51 0.9 1 hCV2084296 rs2853696 hCV7537839 rs1368439 0.51
0.9 1 hCV26465573 rs11209030 hCV29129920 rs6677188 0.51 0.9 0.9607
hCV26465573 rs11209030 hCV31222784 rs11209031 0.51 0.9 0.9628
hCV26465573 rs11209030 hCV31222785 rs12045232 0.51 0.9 0.9607
hCV2720238 rs11209032 hCV2720231 rs11209034 0.51 0.9 0.9774
hCV2720238 rs11209032 hCV2720233 rs11209033 0.51 0.9 0.9769
hCV2720238 rs11209032 hCV3277187 rs7546245 0.51 0.9 0.9304
hCV2720238 rs11209032 hCV3277191 rs12119179 0.51 0.9 0.9541
hCV27467945 rs3181225 hCV15824051 rs2853697 0.51 0.9 1 hCV27467945
rs3181225 hCV16044033 rs2569254 0.51 0.9 1 hCV27467945 rs3181225
hCV2084260 rs13153734 0.51 0.9 0.9034 hCV27467945 rs3181225
hCV2084282 rs2099327 0.51 0.9 0.9338 hCV27467945 rs3181225
hCV27467946 rs3181226 0.51 0.9 1 hCV27467945 rs3181225 hCV31985611
rs13161132 0.51 0.9 0.9259 hCV27952715 rs4655692 hCV2990015
rs7528924 0.51 0.9 1 hCV2989999 rs1343152 hCV2990001 rs12030948
0.51 0.9 1 hCV2990018 rs7530511 hCV16078411 rs2863212 0.51 0.9
0.9186 hCV2990018 rs7530511 hCV27868367 rs4655530 0.51 0.9 0.9192
hCV2990018 rs7530511 hCV27868368 rs4655693 0.51 0.9 1 hCV2990018
rs7530511 hCV31222825 rs10889671 0.51 0.9 0.9192 hCV30279129
rs10489629 hCV2990017 rs7518660 0.51 0.9 0.9444 hCV30611467
rs6869411 hCV31985588 rs6878967 0.51 0.9 1 hCV30611467 rs6869411
hCV31985590 rs11738529 0.51 0.9 1 hCV30611467 rs6869411 hDV70836317
rs17056706 0.51 0.9 1 hCV31222784 rs11209031 hCV26465573 rs11209030
0.51 0.9 0.9628 hCV31222784 rs11209031 hCV29129920 rs6677188 0.51
0.9 1 hCV31222784 rs11209031 hCV30423493 rs7539328 0.51 0.9 0.9266
hCV31222784 rs11209031 hCV31222785 rs12045232 0.51 0.9 1
hCV31222786 rs1857292 hCV11283811 rs4655536 0.51 0.9 1 hCV31222786
rs1857292 hCV2720226 rs2863209 0.51 0.9 1 hCV31222825 rs10889671
hCV27868367 rs4655530 0.51 0.9 1 hCV31222825 rs10889671 hCV27868368
rs4655693 0.51 0.9 0.9192 hCV31222825 rs10889671 hCV2990018
rs7530511 0.51 0.9 0.9192 hCV31222826 rs10789229 hCV31222830
rs12751814 0.51 0.9 0.9808 hCV31985602 rs3213119 hCV2084294
rs3213120 0.51 0.9 1 hCV7537756 rs1368437 hCV1030157 rs254837 0.51
0.9 0.9396 hCV7537756 rs1368437 hCV25633374 rs12520035 0.51 0.9 1
hCV7537756 rs1368437 hCV28001193 rs4921466 0.51 0.9 0.9425
hCV7537839 rs1368439 hCV11316602 rs1865014 0.51 0.9 1 hCV7537839
rs1368439 hCV2084251 rs10515780 0.51 0.9 1 hCV7537839 rs1368439
hCV2084252 rs10866711 0.51 0.9 1 hCV7537839 rs1368439 hCV2084259
rs7708700 0.51 0.9 1 hCV7537839 rs1368439 hCV2084263 rs10515782
0.51 0.9 1 hCV7537839 rs1368439 hCV2084265 rs7736656 0.51 0.9 1
hCV7537839 rs1368439 hCV2084266 rs10042630 0.51 0.9 0.9705
hCV7537839 rs1368439 hCV2084274 rs1433047 0.51 0.9 1 hCV7537839
rs1368439 hCV2084277 rs6874870 0.51 0.9 1 hCV7537839 rs1368439
hCV2084296 rs2853696 0.51 0.9 1 hCV7537839 rs1368439 hCV27936085
rs4921437 0.51 0.9 0.9422 hCV7537839 rs1368439 hCV30629526
rs4921458 0.51 0.9 1 hCV8367042 rs1008193 hCV11728628 rs2000252
0.51 0.9 0.9771 hCV8367042 rs1008193 hCV29503362 rs6682033 0.51 0.9
1 hCV8367043 rs1343151 hDV81067815 rs41396545 0.51 0.9 0.9168
hDV71045748 rs6894567 hCV15803290 rs2421047 0.51 0.9 0.9527
hDV71045748 rs6894567 hCV15879826 rs2288831 0.51 0.9 0.9496
hDV71045748 rs6894567 hCV2084270 rs2082412 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV2084293 rs3212227 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV27471935 rs3212217 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV27486507 rs3212219 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV27508808 rs3212218 0.51 0.9 0.9483
hDV71045748 rs6894567 hCV27883435 rs4921442 0.51 0.9 0.9026
hDV71045748 rs6894567 hCV29349409 rs6859018 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV29619986 rs10072923 0.51 0.9 0.9527
hDV71045748 rs6894567 hCV29927086 rs3213094 0.51 0.9 0.9476
hDV71045748 rs6894567 hCV30449508 rs3212220 0.51 0.9 0.9527
hDV71045748 rs6894567 hCV30557642 rs10056599 0.51 0.9 0.9476
hDV71045748 rs6894567 hDV75439995 rs3213097 0.51 0.9 0.9523
TABLE-US-00005 TABLE 5
rs7530511-rs11465804-rs10889671-rs11209026-rs1857292 haplotypes
Sample Set 1 Sample Set 2 Sample Set 3 No. (Frequency) in No.
(Frequency) in No. (Frequency) in Haplotype.sup.a,b Case Control
Case Control Case Control CTGGA 754(0.818) 704(0.769) 791(0.802)
747(0.755) 795(0.828) 645(0.760) TTAGT 69(0.075) 103(0.112)
68(0.069) 82(0.083) 74(0.077) 78(0.092) CGGAA 36(0.039) 47(0.051)
45(0.046) 79(0.080) 33(0.034) 52(0.061) CTGGT 31(0.034) 21(0.023)
31(0.031) 36(0.036) 22(0.023) 28(0.033) TTAGA 23(0.025) 26(0.028)
20(0.020) 27(0.027) 28(0.029) 31(0.037) Other 9(0.010) 15(0.016)
31(0.031) 19(0.019) 8(0.008) 14(0.017) .sup.aHaplotype estimates
were from the pseudo-Gibbs algorithm in the SNPAnalyzer program.
.sup.bThese haplotypes consist of SNPs: rs7530511, rs11465804,
rs10889671, rs11209026 and rs1857292, respectively.
TABLE-US-00006 Sample Set 1 Sample Set 2 Sample Set 3 No.
(Frequency) in No. (Frequency) in No. (Frequency) in Combined
Haplotype Case Control OR Case Control OR Case Control OR
P.sub.comb.sup.d Protective.sup.c 105(0.114) 150(0.164) 113(0.115)
161(0.163) 107(0.112) 130(0.153) All Other 817(0.886) 766(0.836)
0.66 873(0.885) 829(0.837) 0.67 853(0.889) 718(0.847) 0.69 4.32E-07
.sup.cTTAGT and CGGAA haplotypes combined.
.sup.dContinuity-corrected Mantel-Haenszel P-value.
TABLE-US-00007 TABLE 6 rs7530511-rs10889671-rs11209026 haplotypes
Sample Set 1 Sample Set 2 Sample Set 3 No. (Frequency) in No.
(Frequency) in No. (Frequency) in Combined Haplotype.sup.a,b Case
Control Case Control Case Control P.sub.comb.sup.C CGG 783(0.852)
727(0.795) 830(0.844) 787(0.798) 818(0.855) 677(0.801) 3.88E-08 TAG
91(0.099) 128(0.140) 88(0.090) 108(0.110) 100(0.105) 107(0.127) CGA
39(0.042) 54(0.059) 51(0.052) 86(0.087) 33(0.035) 55(0.065) Other
6(0.007) 5(0.006) 14(0.014) 5(0.005) 6(0.006) 6(0.007)
.sup.aHaplotype estimates were from the pseudo-Gibbs algorithm in
the SNPAnalyzer program. .sup.bThese haplotypes consist of SNPs:
rs7530511, rs10889671, and rs11209026, respectively.
.sup.cContinuity-corrected Mantel-Haenszel P-value for TAG +
CGA
TABLE-US-00008 TABLE 7 Twenty-three marker haplotypes Sample Set 1
Sample Set 2 Haplotype.sup.a,b Case Control OR Pc Case Control OR
Pc CTGGTGCTGGGTGCCCTACCAAA 248 217 1.18 0.133 266 252 1.07 0.506
CCGATAACGGTTAGCCTCCAACG 181 184 0.97 0.815 206 200 1.04 0.781
TTAATGACAGTTGCTCTCCCTAG 65 100 0.62 0.0042 61 75 0.80 0.215
CCGATAATGGTTGCTATCTCAAG 85 76 1.12 0.510 60 72 0.82 0.281
CTAATGATGGGAGCCCTCCCAAG 79 62 1.28 0.162 76 70 1.09 0.667
CCGAGGCTGATTACCCTCCCAAG 36 47 0.75 0.217 47 75 0.61 0.0089
CTGGTGCTGGGTGCCCTACCAAG 35 38 0.91 0.176 37 36 1.03 1.000
CCGATAATGGTTGCTATCTAACG 23 32 0.70 0.220 25 26 0.96 0.888
CCGATAACGGTTAGCCTCCCAAG 21 23 0.90 0.762 34 30 1.14 0.703 Other 151
135 1.13 0.368 174 148 1.21 0.128 Sample Set 3 Combined Analysis
Haplotype.sup.a,b Case Control OR Pc OR.sup.d P.sup.e
CTGGTGCTGGGTGCCCTACCAAA 280 220 1.18 0.127 1.139 0.034
CCGATAACGGTTAGCCTCCAACG 215 157 1.27 0.047 1.081 0.252
TTAATGACAGTTGCTCTCCCTAG 73 77 0.82 0.268 0.736 0.0022
CCGATAATGGTTGCTATCTCAAG 65 69 0.82 0.281 0.921 0.440
CTAATGATGGGAGCCCTCCCAAG 75 52 1.30 0.168 1.216 0.064
CCGAGGCTGATTACCCTCCCAAG 31 51 0.52 0.0063 0.618 0.000113
CTGGTGCTGGGTGCCCTACCAAG 36 34 0.93 0.808 0.955 0.792
CCGATAATGGTTGCTATCTAACG 37 26 1.27 0.372 0.961 0.860
CCGATAACGGTTAGCCTCCCAAG 20 17 1.04 1.000 1.035 0.906 Other 128 145
0.75 0.030 1.017 0.849 .sup.aHaplotypes built on: rs7530511,
rs10489629, rs4655692, rs2201841, rs11465804, rs10489628,
rs1343152, rs10789229, rs10889671, rs11209026, rs10889674,
rs12085634, rs1343151, rs1008193, rs6693831, rs10889675,
rs11465827, rs10889677, rs4655531, rs11209030, rs1857292,
rs11209031, and rs11209032, respectively. .sup.bPseudo-Gibbs
sampling algorithm in SNPAnalyzer used .sup.cFisher's Exact test
.sup.dMantel-Haenszel common odds ratio .sup.eContinuity-corrected
Mantel-Haenszel P-value
TABLE-US-00009 TABLE 8 Twelve marker reduced haplotypes Sample Set
1 Sample Set 2 Haplotype.sup.a,b Cases Controls OR P-value.sup.c
Cases Controls OR P-value.sup.c GGGTCCTACCAA 256 217 1.374 0.055
270 255 1.125 0.476 AATTGCTCCACG 190 186 1.092 0.954 213 202 1.105
0.581 AGTTCCTCCCAG 116 156 0.729 0.0070 124 174 0.668 0.0017
AATTCATCTCAG 90 75 1.291 0.255 71 77 0.932 0.609 AGGACCTCCCAG 85 66
1.394 0.127 78 74 1.082 0.800 GGGTCCTACCAG 36 39 0.961 0.724 38 38
1.019 1.000 AATTGCTCCCAG 34 42 0.836 0.350 56 57 1.000 0.923
AATTCATCTACG 24 34 0.727 0.183 28 26 1.100 0.890 Other 93 99 0.977
0.595 108 81 1.421 0.047 Sample Set 3 Haplotype.sup.a,b Cases
Controls OR P-value.sup.c GGGTCCTACCAA 280 225 1.238 0.227
AATTGCTCCACG 220 161 1.372 0.043 AGTTCCTCCCAG 114 143 0.676 0.0029
AATTCATCTCAG 76 72 0.963 0.668 AGGACCTCCCAG 77 48 1.530 0.077
GGGTCCTACCAG 38 35 0.994 0.905 AATTGCTCCCAG 32 38 0.760 0.223
AATTCATCTACG 37 27 1.270 0.524 Other 86 99 0.766 0.062 Frequency
Haplotype Case Control OR.sup.d P.sup.e AGTTCCTCCCAG 0.123 0.172
0.677 3.19E-07 All Other 0.877 0.828 .sup.aHaplotypes built on:
rs2201841, rs10489628, 10889674, rs12085634, rs1008193, rs10889675,
rs11465827, rs10889677, rs4655531, rs11209030, rs11209031, and
rs11209032, respectively. .sup.bHaplotype estimates were from the
pseudo-Gibbs algorithm in the SNPAnalyzer program. .sup.cFisher's
Exact test .sup.dMantel-Haenszel Common OR
.sup.eContinuity-Corrected Mantel-Haenszel P-value
TABLE-US-00010 TABLE 9 Indiv control_ case_ 9-SNP freq freq SNP set
haplotype (counts) (counts) Hap.P rs2546892 S0048 GAGCCATTG 0.170
(156) 0.119 (111) 0.001739 rs1433048 S0056A GAGCCATTG 0.189 (188)
0.097 (96) 8.51E-09 rs6894567 A0019 GAGCCATTG 0.164 (138) 0.121
(116) 0.011771 rs17860508 rs7709212 Comb P 2.2E-11 rs953861
rs6869411 rs1833754 rs6861600
TABLE-US-00011 TABLE 10 control case freq freq SNP set S0048
(counts) (counts) Hap.P Global rs1368437 GGTGTTTTC 0.022 (20) 0.028
(26) 0.460695 0.003899 rs2082412 CGTATTCGC 0.176 (161) 0.187 (174)
0.510331 0.003899 rs7730390 CGTGGTCGT 0.190 (174) 0.205 (191)
0.450394 0.003899 rs3181225 GGTGTTCGC 0.069 (63) 0.090 (84)
0.097427 0.003899 rs1368439 CACGTGCGC 0.207 (190) 0.144 (134)
0.000429 0.003899 rs3212227 CGTGTTCGC 0.324 (297) 0.343 (320)
0.383258 0.003899 rs3213120 Other 0.013 (11) 0.004 (3) rs3213119
control_ case_ freq freq rs2853696 S0056A (counts) (counts) Hap.P
Global CGTATTCGC 0.176 (175) 0.173 (172) 8.12E-01 5.28E-05
GGTGTTCGC 0.067 (66) 0.101 (100) 4.01E-03 5.28E-05 CGTGGTCGT 0.181
(180) 0.226 (225) 1.42E-02 5.28E-05 CACGTGCGC 0.223 (221) 0.140
(139) 3.48E-06 5.28E-05 CGTGTTCGC 0.308 (306) 0.325 (324) 4.58E-01
5.28E-05 GGTGTTTTC 0.032 (31) 0.026 (25) 3.99E-01 5.28E-05 Other
0.013 (13) 0.009 (8) control_ case_ freq freq A0019 (counts)
(counts) Hap.P Global GGTGTTTTC 0.030 (25) 0.021 (20) 0.222102
0.023735 CGTATTCGC 0.171 (145) 0.165 (158) 0.714954 0.023735
GGTGTTCGC 0.074 (62) 0.083 (79) 0.48817 0.023735 CGTGGTCGT 0.175
(147) 0.217 (208) 0.02158 0.023735 CACGTGCGC 0.212 (179) 0.162
(155) 0.007201 0.023735 CGTGTTCGC 0.331 (280) 0.337 (324) 0.793763
0.023735 Other 0.007 (6) 0.015 (14) CACGTGCGC Comb P 1.03E-09
Global Comb P 2.84E-07
TABLE-US-00012 TABLE 11 frequency of frequency of Genotyped Odds
Major Minor minor allele minor allele Marker Gene or Imputed
P-value Ratio OR95l OR95u allele allele in cases in controls
rs6859018 Imputation 1.31E-10 0.636 0.555 0.731 G A 0.150 0.216
rs10072923 Imputation 1.41E-10 0.637 0.555 0.731 T C 0.150 0.217
rs2421047 IL12B Imputation 2.05E-10 0.640 0.558 0.734 G A 0.150
0.216 rs4921442 UBLCP1 Imputation 2.52E-10 0.641 0.558 0.735 C G
0.151 0.217 rs10056599 Imputation 2.55E-10 0.642 0.559 0.736 T G
0.152 0.217 rs3213097 IL12B Imputation 2.60E-10 0.641 0.559 0.736 A
T 0.150 0.216 rs3212218 IL12B Imputation 2.78E-10 0.642 0.559 0.737
C A 0.151 0.216 rs3212219 IL12B Imputation 3.02E-10 0.642 0.560
0.737 C A 0.151 0.216 rs3212227 IL12B Genotyping 3.44E-10 0.643
0.560 0.738 T G 0.150 0.215 rs7730390 Genotyping 4.08E-10 0.644
0.561 0.739 T C 0.151 0.216 rs3213093 IL12B Genotyping 4.30E-10
0.645 0.562 0.740 C T 0.151 0.215 rs3213094 IL12B Imputation
5.77E-10 0.649 0.566 0.744 C T 0.155 0.219 rs3212220 IL12B
Genotyping 9.02E-10 0.650 0.566 0.746 G T 0.152 0.215 rs2082412
Genotyping 1.26E-09 0.652 0.568 0.748 G A 0.152 0.214 rs3212217
IL12B Genotyping 1.26E-09 0.652 0.568 0.749 C G 0.152 0.215
rs6861600 Genotyping 3.26E-09 0.701 0.623 0.788 C G 0.248 0.320
rs12522665 Imputation 4.14E-09 0.703 0.624 0.790 C T 0.249 0.320
rs6887695 Genotyping 5.26E-09 0.704 0.626 0.792 G C 0.249 0.320
rs6556412 Imputation 6.25E-09 0.702 0.623 0.791 G A 0.253 0.325
rs6864071 Imputation 6.25E-09 0.702 0.623 0.791 G A 0.253 0.325
rs4379175 Imputation 6.25E-09 0.702 0.623 0.791 G T 0.253 0.325
rs6894567 IL12B Genotyping 7.52E-09 0.665 0.579 0.764 A G 0.150
0.210 rs7704367 Genotyping 8.26E-09 0.707 0.629 0.796 A C 0.250
0.320 rs7725339 Imputation 9.21E-09 0.704 0.625 0.794 G T 0.253
0.324 rs11135059 Imputation 1.17E-08 0.706 0.626 0.796 G A 0.254
0.324 rs7709212 Genotyping 5.42E-08 0.727 0.648 0.815 T C 0.272
0.339 rs6556411 Imputation 2.59E-06 1.318 1.175 1.479 T G 0.366
0.306 rs4244437 Imputation 3.41E-06 1.314 1.171 1.474 A G 0.366
0.307 rs983825 Imputation 3.41E-06 1.314 1.171 1.474 A C 0.366
0.307 rs6556416 Imputation 9.68E-06 1.306 1.160 1.471 C A 0.354
0.297 rs6556405 RNF145 Imputation 4.20E-05 0.778 0.690 0.877 T C
0.233 0.280 rs918520 Genotyping 7.28E-05 1.289 1.137 1.462 C G
0.252 0.207 rs7715173 Imputation 8.49E-05 0.770 0.675 0.877 T C
0.183 0.225 rs6870828 Imputation 9.25E-05 1.234 1.110 1.371 T C
0.514 0.462 rs7719425 Genotyping 0.000106687 0.773 0.678 0.880 T C
0.184 0.225 rs1422877 Imputation 0.000112734 0.798 0.711 0.895 A G
0.326 0.378 rs1549922 Imputation 0.000132703 0.814 0.732 0.904 G A
0.448 0.500 rs1473247 RNF145 Imputation 0.000145486 0.793 0.704
0.894 T C 0.237 0.282 rs4921483 Imputation 0.000145879 1.314 1.141
1.513 G A 0.200 0.161 rs1897565 RNF145 Genotyping 0.000150046 0.794
0.704 0.894 T C 0.235 0.279 rs6888950 RNF145 Genotyping 0.000151216
0.793 0.703 0.894 T G 0.235 0.279 rs12651787 Imputation 0.000169251
0.803 0.717 0.900 T C 0.326 0.376 rs4921493 Imputation 0.000251817
0.809 0.722 0.906 T C 0.324 0.373 rs10076782 RNF145 Genotyping
0.000288586 0.801 0.711 0.903 G A 0.238 0.280 rs1363670 Imputation
0.000361505 1.285 1.120 1.475 G C 0.204 0.168 rs1984811 Imputation
0.000371323 1.250 1.105 1.413 A G 0.276 0.234 rs1422878 Genotyping
0.000371662 0.818 0.733 0.914 C T 0.317 0.362 rs953861 Genotyping
0.000388002 1.283 1.118 1.473 A G 0.205 0.169 rs1157509 Imputation
0.000459256 1.280 1.115 1.469 G A 0.203 0.168 rs1157510 Imputation
0.000459256 1.280 1.115 1.469 C T 0.203 0.168 rs11749573 Imputation
0.000459256 1.280 1.115 1.469 A G 0.203 0.168 rs9313808 Imputation
0.000459256 1.280 1.115 1.469 G A 0.203 0.168 rs2853694 IL12B
Genotyping 0.000544359 0.830 0.747 0.923 G T 0.449 0.495 rs4921499
Imputation 0.000588348 1.232 1.094 1.388 G A 0.286 0.246 rs4921500
Imputation 0.000588348 1.232 1.094 1.388 G A 0.286 0.246 rs7702534
Imputation 0.000588348 1.232 1.094 1.388 G T 0.286 0.246 rs254843
Imputation 0.000687505 1.258 1.102 1.437 C T 0.227 0.190 rs4921504
Imputation 0.000705248 0.784 0.681 0.902 C G 0.181 0.217 rs2421186
Imputation 0.000705248 0.784 0.681 0.902 A C 0.181 0.217 rs254852
Imputation 0.000817419 1.254 1.098 1.432 A T 0.223 0.188 rs254850
Imputation 0.000817419 1.254 1.098 1.432 C T 0.223 0.188 rs254839
Imputation 0.000836466 1.256 1.099 1.436 T A 0.225 0.189 rs4921200
Imputation 0.000836466 1.256 1.099 1.436 A T 0.225 0.189 rs4921496
Genotyping 0.000990418 1.220 1.084 1.373 C T 0.287 0.249 rs10042630
UBLCP1 Imputation 0.001080853 1.249 1.093 1.427 T A 0.218 0.184
rs4921458 Imputation 0.001132692 1.248 1.092 1.426 C T 0.218 0.184
rs4921437 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423 C T 0.218
0.184 rs10515780 UBLCP1 Imputation 0.001252363 1.245 1.090 1.423 G
C 0.218 0.184 rs10866711 UBLCP1 Imputation 0.001252363 1.245 1.090
1.423 C T 0.218 0.184 rs7708700 UBLCP1 Imputation 0.001252363 1.245
1.090 1.423 C T 0.218 0.184 rs10515782 UBLCP1 Imputation
0.001252363 1.245 1.090 1.423 T C 0.218 0.184 rs7736656 UBLCP1
Imputation 0.001252363 1.245 1.090 1.423 G A 0.218 0.184 rs4921230
Genotyping 0.001269997 0.813 0.717 0.922 C T 0.209 0.245 rs12657996
Imputation 0.001330019 0.790 0.684 0.912 G A 0.172 0.207 rs1368439
IL12B Genotyping 0.001332138 1.243 1.089 1.420 T G 0.217 0.183
rs1865014 Imputation 0.001433642 1.241 1.087 1.418 C T 0.216 0.182
rs6874870 Imputation 0.001792749 1.236 1.082 1.412 C T 0.216 0.183
rs2853696 IL12B Genotyping 0.001902523 1.234 1.081 1.410 C T 0.217
0.184 rs1433047 Imputation 0.002006695 1.233 1.080 1.409 C T 0.216
0.183 rs1433048 IL12B Genotyping 0.00236978 1.230 1.076 1.406 A G
0.218 0.185 rs270659 Imputation 0.00276249 1.238 1.076 1.423 T C
0.192 0.162 rs13178603 RNF145 Imputation 0.004508011 1.212 1.061
1.384 G C 0.217 0.187 rs270661 Genotyping 0.004825491 1.207 1.059
1.376 C T 0.215 0.185 rs13158488 RNF145 Imputation 0.004904697
1.209 1.059 1.380 T C 0.216 0.186 rs17663721 RNF145 Imputation
0.005027418 1.208 1.059 1.379 T C 0.216 0.186 rs11574790 IL12B
Imputation 0.005211623 1.318 1.086 1.600 G A 0.092 0.071 rs2195940
IL12B Imputation 0.006176876 1.311 1.080 1.591 C T 0.092 0.072
rs2116821 Imputation 0.011425124 0.871 0.782 0.969 C T 0.367 0.399
rs7732511 Imputation 0.012287922 1.216 1.043 1.417 G A 0.160 0.136
rs1433046 UBLCP1 Imputation 0.015431773 0.876 0.786 0.975 T C 0.370
0.402 rs194228 Imputation 0.015866292 0.876 0.787 0.975 G A 0.369
0.401 rs2420825 UBLCP1 Imputation 0.015866292 0.876 0.787 0.975 T C
0.369 0.401 rs3734104 UBLCP1 Imputation 0.015866292 0.876 0.787
0.975 G C 0.369 0.401 rs17665189 UBLCP1 Imputation 0.015866292
0.876 0.787 0.975 T G 0.369 0.401 rs17860508 Genotyping 0.01770095
0.882 0.794 0.978 T C 0.465 0.497 rs254837 Imputation 0.018638426
1.234 1.036 1.470 C G 0.113 0.094 rs11746138 Imputation 0.025056654
1.190 1.022 1.385 C T 0.157 0.136 rs11747112 Imputation 0.025056654
1.190 1.022 1.385 C G 0.157 0.136 rs12652431 Imputation 0.027069579
1.213 1.022 1.440 A G 0.122 0.104 rs1368437 UBLCP1 Genotyping
0.02847955 1.211 1.020 1.437 C G 0.118 0.100 rs12520035 UBLCP1
Imputation 0.033981552 1.202 1.014 1.425 A G 0.118 0.101 rs270654
Genotyping 0.036760864 1.198 1.011 1.420 T C 0.119 0.102 rs919766
IL12B Genotyping 0.040074923 1.193 1.008 1.412 A C 0.122 0.105
rs4921466 Imputation 0.041237398 1.195 1.007 1.418 T C 0.117 0.100
rs3181224 Imputation 0.048412617 1.184 1.001 1.401 A G 0.122 0.106
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20160222450A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20160222450A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References