U.S. patent application number 11/781679 was filed with the patent office on 2008-06-05 for genetic analysis systems and methods.
Invention is credited to Melissa Floren Filippone, Dietrich A. Stephan.
Application Number | 20080131887 11/781679 |
Document ID | / |
Family ID | 39476259 |
Filed Date | 2008-06-05 |
United States Patent
Application |
20080131887 |
Kind Code |
A1 |
Stephan; Dietrich A. ; et
al. |
June 5, 2008 |
Genetic Analysis Systems and Methods
Abstract
The present invention provides methods of assessing an
individual's genotype correlations by analyzing the individual's
genomic profile to a database of medically relevant genetic
variations that have been established to correlate to a
phenotype.
Inventors: |
Stephan; Dietrich A.;
(Phoenix, AZ) ; Filippone; Melissa Floren; (New
York, NY) |
Correspondence
Address: |
WILSON SONSINI GOODRICH & ROSATI
650 PAGE MILL ROAD
PALO ALTO
CA
94304-1050
US
|
Family ID: |
39476259 |
Appl. No.: |
11/781679 |
Filed: |
July 23, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60868066 |
Nov 30, 2006 |
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60951123 |
Jul 20, 2007 |
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Current U.S.
Class: |
435/6.11 ;
702/20; 707/999.01 |
Current CPC
Class: |
G16B 20/00 20190201;
G16B 50/00 20190201 |
Class at
Publication: |
435/6 ; 702/20;
707/10 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; G06F 17/30 20060101 G06F017/30; G06F 19/00 20060101
G06F019/00 |
Claims
1. A method of assessing genotype correlations of an individual
comprising: a) obtaining a genetic sample of the individual; b)
generating a genomic profile for the individual; c) determining the
individual's genotype correlations with phenotypes by comparing the
individual's genomic profile to a current database of human
genotype correlations with phenotypes; d) reporting the results
from step c) to the individual or a health care manager of the
individual; e) updating the database of human genotype correlations
with an additional human genotype correlation as the additional
human genotype correlation becomes known; and f) updating the
individual's genotype correlations by comparing the individual's
genomic profile of step c) or a portion thereof to the additional
human genotype correlation and determining an additional genotype
correlation of the individual; and g) reporting the results from
step f) to the individual or the health care manager of the
individual.
2. The method of claim 1, wherein the reporting comprises
transmission of the results over a network.
3. The method of claim 1, wherein the reporting of the results is
through an on-line portal.
4. The method of claim 1, wherein the reporting of the results is
by paper or by e-mail.
5. The method of claim 1, wherein the reporting comprises reporting
the results in a secure manner.
6. The method of claim 1, wherein the reporting comprises reporting
the results in a non-secure manner.
7. The method of claim 1, wherein the individual's genomic profile
is deposited into a secure database or vault.
8. The method of claim 1, wherein the individual is a
subscriber.
9. The method of claim 1, wherein the individual is not a
subscriber.
10. The method of claim 1, wherein the genetic sample is DNA.
11. The method of claim 1, wherein the genetic sample is RNA.
12. The method of claim 1, wherein the genomic profile is a single
nucleotide polymorphism genomic profile, the database of human
genotype correlations are human single nucleotide polymorphism
correlations, and the additional human genotype correlation is a
single nucleotide polymorphism correlation.
13. The method of claim 1, wherein the genomic profile comprises
truncations, insertions, deletions or repeats, the database of
human genotype correlations are human truncations, insertions,
deletions or repeats correlations, and the additional human
genotype correlation is a truncation, insertion, deletion or repeat
correlation.
14. The method of claim 1, wherein the genomic profile is of the
individual's entire genome.
15. The method of claim 1, wherein the method comprises assessing 2
or more genotype correlations.
16. The method of claim 1, wherein the method comprises assessing
10 or more genotype correlations.
17. The method of claim 1, wherein the database of human genotype
correlations contains genetic variants in one or more genes listed
in Table 1 and phenotypes correlated with the genetic variants.
18. The method of claim 1, wherein the database of human genotype
correlations contains genetic variants in one or more genes listed
in FIGS. 4, 5, or 6 and phenotypes correlated with the genetic
variants.
19. The method of claim 1, wherein the database of human genotype
correlations contains genetic variants determined from the genomic
profiles of the individuals and previously determined phenotypes
disclosed by the individuals.
20. The method of claim 1, wherein the database of human genotype
correlations contains single nucleotide polymorphisms in the genes
listed in Table 1 or FIGS. 4, 5, or 6, and phenotypes correlated
with the single nucleotide polymorphisms.
21. The method of claim 1, wherein the genetic sample is from a
biological sample selected from the group consisting of blood,
hair, skin, saliva, semen, urine, fecal material, sweat, and buccal
sample.
22. The method of claim 12, wherein the genotype correlations are
correlations of single nucleotide polymorphisms to diseases and
conditions.
23. The method of claim 12, wherein the genotype correlations are
correlations of single nucleotide polymorphisms to phenotypes that
are not medical conditions.
24. The method of claim 13, wherein the genotype correlations are
correlations of truncations, insertions, deletions or repeats to
diseases and conditions.
25. The method of claim 13, wherein the genotype correlations are
correlations of truncations, insertions, deletions or repeats to
phenotypes that are not medical conditions.
26. The method of claim 1, wherein the genomic profile is generated
using a high density DNA micro array.
27. The method of claim 12, wherein the single nucleotide
polymorphism genomic profile is generated using a high density DNA
microarray.
28. The method of claim 1, wherein the genomic profile is generated
using genomic DNA sequencing.
29. The method of claim 12, wherein the single nucleotide
polymorphism genomic profile is generated using genomic DNA
sequencing.
30. The method of claim 21, wherein the genetic sample is genomic
DNA and the biological sample is saliva.
31. A business method of assessing genotype correlations of an
individual comprising: a) obtaining a genetic sample of the
individual; b) generating a genomic profile for the individual; c)
determining the individual's genotype correlations by comparing the
individual's genomic profile to a database of human genotype
correlations; d) providing results of the determining of the
individual's genotype correlations to the individual or a health
care manager of the individual; e) updating the database of human
genotype correlations with an additional human genotype correlation
as the additional human genotype correlation becomes known; f)
updating the individual's genotype correlations by comparing the
individual's genomic profile of step c) or a portion thereof to the
additional human genotype correlation and determining an additional
genotype correlation of the individual; and g) providing results of
the updating of the individual's genotype correlations to the
individual or a health care manager of the individual.
32. The method of claim 31, wherein the providing results comprises
transmission of the results over a network.
33. The method of claim 31, wherein the results are provided
through an on-line portal.
34. The method of claim 31, wherein the results are provided by
paper or by e-mail.
35. The method of claim 33, wherein providing the results comprises
providing the results in a secure manner.
36. The method of claim 33, wherein the reporting comprises
reporting the results in a non-secure manner.
37. The method of claim 31, wherein the individual's genomic
profile is deposited into a secure database or vault.
38. The method of claim 31, wherein the individual is a
subscriber.
39. The method of claim 31, wherein the individual is not a
subscriber.
40. The method of claim 31, wherein the individual or the health
care manager sets preferences for the results that are provided to
the individual or the health care manager.
41. The method of claim 31, comprising further providing the
individual or the health care manager with interpretative and
supportive information of the results.
42. The method of claim 31, wherein the genomic profile is a single
nucleotide polymorphism genomic profile, the database of human
genotype correlations are human single nucleotide polymorphism
correlations, and the additional human genotype correlation is a
single nucleotide polymorphism correlation.
43. The method of claim 31, wherein the genomic profile comprises
truncations, insertions, deletions or repeats, the database of
human genotype correlations are human truncations, insertions,
deletions or repeats correlations, and the additional human
genotype correlation is a truncation, insertion, deletion or repeat
correlation.
44. The method of claim 31, wherein the genomic profile is of the
individual's entire genome.
45. The method of claim 31, wherein the method comprises assessing
2 or more genotype correlations.
46. The method of claim 31, wherein the method comprises assessing
10 or more genotype correlations.
47. The method of claim 31, wherein the genetic sample is obtained
from a biological sample selected from the group consisting of
blood, hair, skin, saliva, semen, urine, fecal material, sweat, and
buccal sample.
48. The method of claim 31, wherein the database of human genotype
correlations contains genetic variants in the genes listed in Table
1 and phenotypes correlated with the genetic variants.
49. The method of claim 31, wherein the database of human genotype
correlations contains genetic variants in the genes listed in FIGS.
4, 5, or 6 and phenotypes correlated with the genetic variants.
50. The method of claim 31, wherein the database of human genotype
correlations contains genetic variants determined from the genomic
profiles of the individuals and previously determined phenotypes
disclosed by the individuals.
51. The method of claim 42, wherein the genotype correlations are
correlations of single nucleotide polymorphisms to diseases and
conditions.
52. The method of claim 42, wherein the genotype correlations are
correlations of single nucleotide polymorphisms to phenotypes that
are not medical conditions.
53. The method of claim 43, wherein the genotype correlations are
correlations of truncations, insertions, deletions or repeats to
diseases and conditions.
54. The method of claim 43, wherein the genotype correlations are
correlations of truncations, insertions, deletions or repeats to
phenotypes that are not medical conditions.
55. The method of claim 31 wherein the genomic profile is generated
using a high density DNA microarray.
56. The method of claim 42, wherein the single nucleotide
polymorphism genomic profile is generated using a high density DNA
microarray.
57. The method of claim 31 wherein the genomic profile is generated
using genomic DNA sequencing.
58. The method of claim 42, wherein the single nucleotide
polymorphism genomic profile is generated using genomic DNA
sequencing.
59. The method of claim 47, wherein the genetic sample is genomic
DNA and the biological sample is saliva.
60. A business method of assessing genotype correlations of an
individual comprising: a) obtaining a genetic sample of the
individual; b) generating a genomic profile for the individual; c)
importing data of the individual's genomic profile; d) determining
the individual's genotype correlations by comparing the
individual's genomic profile to a database of human genotype
correlations; e) providing results of the determining of the
individual's genotype correlations to the individual of a health
care manager of the individual; f) updating the database of human
genotype correlations with an additional human genotype correlation
as the additional human genotype correlation becomes known; g)
updating the individual's genotype correlations by comparing the
individual's genomic profile or a portion thereof to the additional
human genotype correlation and determining an additional genotype
correlation of the individual; and h) providing results of the
updating of the individual's genotype correlations to the
individual or the health care manager of the individual.
61. The method of claim 60, wherein providing the results comprises
providing the results in a secure manner.
62. The method of claim 60, wherein providing the results comprises
transmission of the results over a network.
63. A method comprising: a) providing a rule set comprising rules,
each rule indicating a correlation between at least one genotype
and at least one phenotype; b) providing a data set comprising
genomic profiles of each of a plurality of individuals, wherein
each genomic profile comprises a plurality of genotypes; c)
periodically updating the rule set with at least one new rule,
wherein the at least one new rule indicates a correlation between a
genotype and a phenotype not previously correlated with each other
in the rule set; and d) applying each new rule to the genomic
profile of at least one of the individuals, thereby correlating at
least one genotype with at least one phenotype for the
individual.
64. The method of claim 63 further comprising: e) generating a
report comprising the phenotype profile of the individual.
65. The method of claim 63 further comprising, after step (b), i)
applying the rules of the rule set to the genomic profiles of the
individuals to determine a set of phenotype profiles for the
individuals; and ii) generating a report comprising an initial
phenotype profile of the individual.
66. The method of claim 64 or 65, wherein providing the report
comprises transmission of the report over a network.
67. The method of claim 64 or 65, wherein providing the report
comprises transmission of the report over a network to the
individual or a health care manager of the individual.
68. The method of claim 64 or 65, wherein the report is provided in
a secure manner.
69. The method of claim 64 or 65, wherein the report is provided in
a non-secure manner.
70. The method of claim 64 or 65, wherein the report is provided
through an on-line portal.
71. The method of claim 64 or 65, wherein the report is provided by
paper or e-mail.
72. The method of claim 63, wherein the new rule correlates an
uncorrelated genotype with a phenotype.
73. The method of claim 63, wherein the new rule correlates a
correlated genotype with a phenotype with which it was not
previously correlated in the rule set.
74. The method of claim 63, wherein the new rule modifies a rule in
the rule set.
75. The method of claim 63, wherein the new rule is generated by
correlation of a genotype from the genomic profiles of the
individuals and a previously determined phenotype of the
individuals.
76. The method of claim 63, wherein the rules correlate a plurality
of genotypes with a phenotype.
77. The method of claim 63, wherein applying the new rule further
comprises determining the phenotype profile at least in part based
on a characteristic of the individual selected from ethnicity,
ancestry, geography, gender, age, family history, and previously
determined phenotypes.
78. The method of claim 63, wherein the genotypes comprise
nucleotide repeats, nucleotide insertions, nucleotide deletions,
chromosomal translocations, chromosomal duplications, or copy
number variations.
79. The method of claim 78, wherein the copy number variations are
microsatellite repeats, nucleotide repeats, centromeric repeats, or
telomeric repeats.
80. The method of claim 63, wherein the genotypes comprise single
nucleotide polymorphisms.
81. The method of claim 63, wherein the genotypes comprise
haplotypes and diplotypes.
82. The method of claim 63, wherein the genotypes comprise genetic
markers in linkage disequilibrium with single nucleotide
polymorphisms correlated with a phenotype.
83. The method of claim 63, wherein the phenotype profile indicates
a presence or absence of the quantitative trait or a risk
developing the quantitative trait.
84. The method of claim 63, wherein the phenotype profile indicates
a probability that an individual with a genotype has or will have a
phenotype.
85. The method of claim 84, wherein the probability is high,
moderate, or low.
86. The method of claim 63, wherein the correlations are
curated.
87. The method of claim 63 wherein the rule set comprises at least
20 rules.
88. The method of claim 63 wherein the rule set comprises at least
50 rules.
89. The method of claim 63 wherein the rule set comprises rules
based on the genotype correlations in Table 1.
90. The method of claim 63 wherein the rule set comprises rules
based on the genotype correlations in FIGS. 4, 5, or 6.
91. The method of claim 63, wherein the phenotype comprises a
quantitative trait.
92. The method of claim 91, wherein the quantitative trait
comprises a medical condition.
93. The method of claim 92, wherein the phenotype profiles
indicates a presence or absence of the medical condition, a risk of
developing the medical condition, a prognosis of the medical
condition, an effectiveness of a treatment for the medical
condition, or a response to a treatment of the medical
condition.
94. The method of claim 91, wherein the quantitative trait
comprises a phenotype that is not a medical condition.
95. The method of claim 91, wherein the quantitative trait is
selected from the group consisting of: physical trait,
physiological trait, mental trait, emotional trait, ethnicity,
ancestry, or age.
96. The method of claim 63, wherein the individuals are humans.
97. The method of claim 63, wherein the individuals are
subscribers.
98. The method of claim 63, wherein the individuals are not
subscribers.
99. The method of claim 63, wherein the individuals are
non-humans.
100. The method of claim 63, wherein the genomic profile comprises
at least 100,000 genotypes.
101. The method of claim 63, wherein the genomic profile comprises
at least 400,000 genotypes.
102. The method of claim 63, wherein the genomic profile comprises
at least 900,000 genotypes.
103. The method of claim 63, wherein the genomic profile comprises
at least 1,000,000 genotypes.
104. The method of claim 63, wherein the genomic profile comprises
a substantially complete entire genomic sequence.
105. The method of claim 63, wherein the data set comprises a
plurality of data points, wherein each data point relates to an
individual and comprises a plurality of data elements, wherein the
data elements include at least one element selected from a unique
identifier, genotype information, microarray SNP identification
number, SNP rs number, chromosome position, polymorphic nucleotide,
quality metrics, raw data files, images, extracted intensity
scores, physical data, medical data, ethnicity, ancestry,
geography, gender, age, family history, known phenotypes,
demographic data, exposure data, lifestyle data, and behavior data,
of the individual.
106. The method of claim 63, wherein periodically updating and
applying occurs at least once a year.
107. The method of claim 63, wherein providing the data set
comprises obtaining a genomic profile of each of a plurality of
individuals by: (i) performing a genetic analysis on a genetic
sample from the individuals and (ii) encoding the analysis in
computer readable format.
108. The method of claim 63, wherein the phenotype profile
comprises a monogenic phenotype.
109. The method of claim 63, wherein the phenotype profile
comprises a multigenic phenotype.
110. The method of claim 63, wherein the report comprises an
initial phenotype profile.
111. The method of claim 63, wherein the report comprises an
updated phenotype profile.
112. The method of claim 63, wherein the report further comprises
information on the phenotypes of the phenotype profile selected
from one or more of the following: prevention strategies, wellness
information, therapies, symptom awareness, early detection schemes,
intervention schemes, and refined identification and
sub-classification of the phenotypes in the phenotype profile.
113. The method of claim 63, further comprising: a) adding a new
genomic profile of a new individual into the individual data set;
b) applying the rule set to the genomic profile of the new
individual; and c) generating an initial report of a phenotype
profile for the new individual.
114. The method of claim 63, further comprising: a) adding a new
genomic profile of the individual; b) applying the rule set to the
new genomic profile the individual; and c) generating a new report
of a phenotype profile for the individual.
115. A system comprising: a) a rule set comprising rules, each rule
indicating a correlation between at least one genotype and at least
one phenotype; b) code that periodically updates the rule set with
at least one new rule, wherein the at least one new rule indicates
a correlation between a genotype and a phenotype not previously
correlated with each other in the rule set; c) a database
comprising genomic profiles of a plurality of individuals; d) code
that applies the rule set to the genomic profiles of individuals to
determine phenotype profiles for the individuals; and e) code that
generates reports for each individual.
116. The system of claim 115, wherein the report is transmitted
over a network.
117. The system of claim 115, wherein the report is transmitted
over a network to the individual or health care manager of the
individual.
118. The system of claim 115, wherein the report is provided in a
secure manner.
119. The system of claim 115, wherein the reports is provided in a
non-secure manner.
120. The system of claim 115, wherein the report is provided
through an on-line portal.
121. The system of claim 115, wherein the report is provided by
paper or e-mail.
122. The system of claim 115, further comprising code that notifies
the individual of new or revised correlations.
123. The system of claim 115, further comprising code that notifies
the individual of new or revised rules that can be applied to the
genomic profile of the individual.
124. The system of claim 115, further comprising code that notifies
the individual of new or revised prevention and wellness
information for the phenotypes of the phenotype profile of the
individual.
125. A kit comprising: a) at least one sample collection container;
b) instructions for obtaining a sample from an individual; c)
instructions for accessing a genomic profile of the individual
obtained from the sample through an on-line portal; d) instructions
for accessing a phenotype profile of the individual obtained from
the sample through an on-line portal; and e) packaging for delivery
of the sample collection container to the sample processing
facility.
126. An on-line portal comprising a website where a individual can
access their phenotype profile, wherein the website allows the
individual to do at least one of the following: a) choose the rules
to be applied to the individual's genomic profile; b) view initial
and updated reports on the website; c) print initial and updated
reports from the website; d) save initial and updated reports from
the website onto the individual's computer; e) obtain prevention
and wellness information on the individual's phenotype profile; f)
obtain on-line or telephone-linked genetic counseling; g) extract
information to share with physicians/genetic counselors; h) access
to partner service and product offerings.
127. The on-line portal of claim 126, wherein the information is
transmitted over a network.
128. The on-line portal of claim 126, wherein the information is
transmitted over a network to the individual or health care manager
of the individual.
129. The on-line portal of claim 126 wherein the website is
secure.
130. The on-line portal of claim 126 wherein the website is not
secure.
131. The on-line portal of claim 126 wherein the individual is
presented with one or more options regarding the level of security
of such individuals' information or one or more portions
thereof.
132. The on-line portal of claim 126 wherein the phenotype profile
comprises an actionable medical condition.
133. The on-line portal of claim 126 wherein the phenotype profile
comprises a medical condition with no existing preventive actions
or existing therapies.
134. The on-line portal of claim 126 wherein the phenotype profile
comprises non medical conditions.
135. The on-line portal of claim 126 further comprising a search
engine.
Description
CROSS REFERENCE
[0001] This application claims the benefit of U.S. Provisional
Application Nos. 60/868,066, filed Nov. 30, 2006, and 60/951,123,
filed Jul. 20, 2007, which are incorporated herein by reference in
their entirety.
BACKGROUND OF THE INVENTION
[0002] Sequencing of the human genome and other recent developments
in human genomics has revealed that the genomic makeup between any
two humans has over 99.9% similarity. The relatively small number
of variations in DNA between individuals gives rise to differences
in phenotypic traits, and is related to many human diseases,
susceptibility to various diseases, and response to treatment of
disease. Variations in DNA between individuals occur in both coding
and non-coding regions, and include changes in bases at a
particular locus in genomic DNA sequences, as well as insertions
and deletions of DNA. Changes that occur at single base positions
in the genome are referred to as single nucleotide polymorphisms,
or "SNPs."
[0003] While SNPs are relatively rare in the human genome, they
account for a majority of DNA sequence variations between
individuals, occurring approximately once every 1,200 base pairs in
the human genome (see International HapMap Project,
www.hapmap.org). As more human genetic information becomes
available, the complexity of SNPs is beginning to be understood. In
turn, the occurrences of SNPs in the genome are becoming correlated
to the presence of and/or susceptibility to various diseases and
conditions.
[0004] As these correlations and other advances in human genetics
are being made, medicine and personal health in general are moving
toward a customized approach in which a patient will make
appropriate medical and other choices in consideration of his or
her genomic information, among other factors. Thus, there is a need
to provide individuals and their care-givers with information
specific to the individual's personal genome toward providing
personalized medical and other decisions.
SUMMARY OF THE INVENTION
[0005] The present invention provides a method of assessing an
individual's genotype correlations comprising: a) obtaining a
genetic sample of the individual, b) generating a genomic profile
for the individual, c) determining the individual's genotype
correlations with phenotypes by comparing the individual's genomic
profile to a current database of human genotype correlations with
phenotypes, d) reporting the results from step c) to the individual
or a health care manager of the individual, e) updating the
database of human genotype correlations with an additional human
genotype correlation as the additional human genotype correlation
becomes known, f) updating the individual's genotype correlations
by comparing the individual's genomic profile from step c) or a
portion thereof to the additional human genotype correlation and
determining an additional genotype correlation of the individual,
and g) reporting the results from step f) to the individual or the
health care manager of the individual.
[0006] The present invention further provides a business method of
assessing genotype correlations of an individual comprising: a)
obtaining a genetic sample of the individual; b) generating a
genomic profile for the individual; c) determining the individual's
genotype correlations by comparing the individual's genomic profile
to a database of human genotype correlations; d) providing results
of the determining of the individual's genotype correlations to the
individual in a secure manner; e) updating the database of human
genotype correlations with an additional human genotype correlation
as the additional human genotype correlation becomes known; f)
updating the individual's genotype correlations by comparing the
individual's genomic profile or a portion thereof to the additional
human genotype correlation and determining an additional genotype
correlation of the individual; and g) providing results of the
updating of the individual's genotype correlations to the
individual of the health care manager of the individual.
[0007] Another aspect of the present invention is a method
generating a phenotype profile for an individual comprising: a)
providing a rule set comprising rules, each rule indicating a
correlation between at least one genotype and at least one
phenotype, b) providing a data set comprising genomic profiles of
each of a plurality of individuals, wherein each genomic profile
comprises a plurality of genotypes; c) periodically updating the
rule set with at least one new rule, wherein the at least one new
rule indicates a correlation between a genotype and a phenotype not
previously correlated with each other in the rule set; d) applying
each new rule to the genomic profile of at least one of the
individuals, thereby correlating at least one genotype with at
least one phenotype for the individual, and optionally, e)
generating a report comprising the phenotype profile of the
individual.
[0008] The present invention also provides a system comprising a) a
rule set comprising rules, each rule indicating a correlation
between at least one genotype and at least one phenotype; b) code
that periodically updates the rule set with at least one new rule,
wherein the at least one new rule indicates a correlation between a
genotype and a phenotype not previously correlated with each other
in the rule set; c) a database comprising genomic profiles of a
plurality of individuals; d) code that applies the rule set to the
genomic profiles of individuals to determine phenotype profiles for
the individuals; and e) code that generates reports for each
individual.
[0009] Another aspect of the present invention is transmission over
a network, in a secure or non-secure manner, the methods and
systems described above.
INCORPORATION BY REFERENCE
[0010] All publications and patent applications mentioned in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a flow chart illustrating aspects of the method
herein.
[0012] FIG. 2 is an example of a genomic DNA quality control
measure.
[0013] FIG. 3 is an example of a hybridization quality control
measure.
[0014] FIG. 4 are tables of representative genotype correlations
from published literature with test SNPs and effect estimates. A-I)
represents single locus genotype correlations; J) respresents a two
locus genotype correlation; K) represents a three locus genotype
correlation; L) is an index of the ethnicity and country
abbreviations used in A-K; M) is an index of the abbreviations of
the Short Phenotype Names in A-K, the heritability, and the
references for the heritability.
[0015] FIG. 5A-J are tables of representative genotype correlations
with effect estimates.
[0016] FIG. 6A-F are tables of representative genotype correlations
and estimated relative risks.
[0017] FIG. 7 is a sample report.
[0018] FIG. 8 is a schematic of a system for the analysis and
transmission of genomic and phenotype profiles over a network.
[0019] FIG. 9 is a flow chart illustrating aspects of the business
method herein
DETAILED DESCRIPTION
[0020] The present invention provides methods and systems for
generating phenotype profiles based on a stored genomic profile of
an individual or group of individuals, and for readily generating
original and updated phenotype profiles based on the stored genomic
profiles. Genomic profiles are generated by determining genotypes
from biological samples obtained from individuals. Biological
samples obtained from individuals may be any sample from which a
genetic sample may be derived. Samples may be from buccal swabs,
saliva, blood, hair, or any other type of tissue sample. Genotypes
may then be determined from the biological samples. Genotypes may
be any genetic variant or biological marker, for example, single
nucleotide polymorphisms (SNPs), haplotypes, or sequences of the
genome. The genotype may be the entire genomic sequence of an
individual. The genotypes may result from high-throughput analysis
that generates thousands or millions of data points, for example,
microarray analysis for most or all of the known SNPs. In other
embodiments, genotypes may also be determined by high throughput
sequencing.
[0021] The genotypes form a genomic profile for an individual. The
genomic profile is stored digitally and is readily accessed at any
point of time to generate phenotype profiles. Phenotype profiles
are generated by applying rules that correlate or associate
genotypes with phenotypes. Rules can be made based on scientific
research that demonstrates a correlation between a genotype and a
phenotype. The correlations may be curated or validated by a
committee of one or more experts. By applying the rules to a
genomic profile of an individual, the association between an
individual's genotype and a phenotype may be determined. The
phenotype profile for an individual will have this determination.
The determination may be a positive association between an
individual's genotype and a given phenotype, such that the
individual has the given phenotype, or will develop the phenotype.
Alternatively, it may be determined that the individual does not
have, or will not develop, a given phenotype. In other embodiments,
the determination may be a risk factor, estimate, or a probability
that an individual has, or will, develop a phenotype.
[0022] The determinations may be made based on a number of rules,
for example, a plurality of rules may be applied to a genomic
profile to determine the association of an individual's genotype
with a specific phenotype. The determinations may also incorporate
factors that are specific to an individual, such as ethnicity,
gender, lifestyle, age, environment, family medical history,
personal medical history, and other known phenotypes. The
incorporation of the specific factors may be by modifying existing
rules to encompass these factors. Alternatively, separate rules may
be generated by these factors and applied to a phenotype
determination for an individual after an existing rule has been
applied.
[0023] Phenotypes may include any measurable trait or
characteristic, such as susceptibility to a certain disease or
response to a drug treatment. Other phenotypes that may be included
are physical and mental traits, such as height, weight, hair color,
eye color, sunburn susceptibility, size, memory, intelligence,
level of optimism, and general disposition. Phenotypes may also
include genetic comparisons to other individuals or organisms. For
example, an individual may be interested in the similarity between
their genomic profile and that of a celebrity. They may also have
their genomic profile compared to other organisms such as bacteria,
plants, or other animals.
[0024] Together, the collection of correlated phenotypes determined
for an individual comprises the phenotype profile for the
individual. The phenotype profile may be accessible by an on-line
portal. Alternatively, the phenotype profile as it exists at a
certain time may be provided in paper form, with subsequent updates
also provided in paper form. The phenotype profile may also be
provided by an on-line portal. The on-line portal may optionally be
a secure on-line portal. Access to the phenotype profile may be
provided to a subscriber, which is an individual who subscribes to
the service that generates rules on correlations between phenotypes
and genotypes, determines the genomic profile of an individual,
applies the rules to the genomic profile, and generates a phenotype
profile of the individual. Access may also be provided to
non-subscribers, wherein they may have limited access to their
phenotype profile and/or reports, or may have an initial report or
phenotype profile generated, but updated reports will be generated
only with purchase of a subscription. Health care managers and
providers, such as caregivers, physicians, and genetic counselors
may also have access to the phenotype profile.
[0025] In another aspect of the invention the genomic profile may
be generated for subscribers and non-subscribers and stored
digitally but access to the phenotype profile and reports may be
limited to subscribers. In another variation, both subscribers and
non-subscribers may access their genotype and phenotype profiles,
but have limited access, or have a limited report generated, for
non-subscribers, whereas subscribers have full access and may have
a full report generated. In another embodiment, both subscribers
and non-subscribers may have full access initially, or full initial
reports, but only subscribers may access updated reports based on
their stored genomic profile.
[0026] There may also be a basic subscription model. A basic
subscription may provide a phenotype profile where the subscriber
may choose to apply all existing rules to their genomic profile, or
a subset of the existing rules, to their genomihc profile. For
example, they may choose to apply only the rules for disease
phenotypes that are actionable. The basic subscription may have
different levels within the subscription class. For example,
different levels may be dependent on the number of phenotypes a
subscriber wants correlated to their genomic profile, or the number
of people that may access their phenotype profile. Another level of
basic subscription may be to incorporate factors specific to an
individual, such as already known phenotypes such as age, gender,
or medical history, to their phenotype profile.
[0027] Subscribers may also generate reports that have their
phenotype profile as well as information about the phenotypes, such
as genetic and medical information about the phenotype. For
example, the prevalence of the phenotype in the population, the
genetic variant that was used for the correlation, the molecular
mechanism that causes the phenotype, therapies for the phenotype,
treatment options for the phenotype, and preventative actions, may
be included in the report. In other embodiments, the reports may
also include information such as the similarity between an
individual's genotype and that of other individuals, such as
celebrities or other famous people. The information on similarity
may be, but are not limited to, percentage homology, number of
identical variants, and phenotypes that may be similar.
[0028] The report may also provide links to other sites with
further information on the phenotypes, links to on-line support
groups and message boards of people with the same phenotype or one
or more similar phenotypes, links to an on-line genetic counselor
or physician, or links to schedule telephonic or in-person
appointments with a genetic counselor or physician, if the report
is accessed on-line. If the report is in paper form, the
information may be the website location of the aforementioned
links, or the telephone number and address of the genetic counselor
or physician. The subscriber may also choose which phenotypes to
include in their phenotype profile and what information to include
in their report. The phenotype profile and reports may also be
accessible by an individual's health care manager or provider, such
as a caregiver, physician, psychiatrist, psychologist, therapist,
or genetic counselor. The subscriber may be able to choose whether
the phenotype profile and reports, or portions thereof, are
accessible by such individual's health care manager or
provider.
[0029] The present invention may also include a premium level of
subscription. The premium level of subscription maintains their
genomic profile digitally after generation of an initial phenotype
profile and report, and provides subscribers the opportunity to
generate phenotype profiles and reports with updated correlations
from the latest research. As research reveals new correlations
between genotypes and phenotypes, new rules will be developed based
on these new correlations and can be applied to the genomic profile
that is already stored and being maintained. The new rules may
correlate genotypes not previously correlated with any phenotype,
correlate genotypes with new phenotypes, or modify existing
correlations. Subscribers may be informed of new correlations via
e-mail or other electronic means, and if the phenotype is of
interest, they may choose to update their phenotype profile with
the new correlation. Subscribers may choose a subscription where
they pay for each update, or for a number of updates. Another
subscription level may be where a subscriber has their phenotype
profile automatically updated, instead of where the individual
chooses when to update their phenotype profile, whenever a new rule
is generated based on a new correlation.
[0030] In another aspect of the subscription, subscribers may refer
non-subscribers to the service that generates rules on correlations
between phenotypes and genotypes, determines the genomic profile of
an individual, applies the rules to the genomic profile, and
generates a phenotype profile of the individual. Referral by a
subscriber may give the subscriber a reduced price on subscription
to the service, or upgrades to their existing subscriptions.
Referred individuals may have free access for a limited time or
have a discounted subscription price.
[0031] Phenotype profiles and reports may be generated for
individuals that are human and non-human. For example, individuals
may include other mammals, such as bovines, equines, ovines,
canines, or felines. Subscribers, as used herein, are human
individuals who subscribe to a service by purchase or payment for
one or more services. Services may include, but are not limited to,
one or more of the following: having their or another individual's,
such as the subscriber's child or pet, genomic profile determined,
obtaining a phenotype profile, having the phenotype profile
updated, and obtaining reports based on their genomic and phenotype
profile.
[0032] The term "biological sample" refers to any biological sample
from which a genetic sample of an individual can be isolated. As
used herein, a "genetic sample" refers to DNA and/or RNA obtained
or derived from an individual.
[0033] As used herein, the term "genome" is intended to mean the
full complement of chromosomal DNA found within the nucleus of a
human cell. The term "genomic DNA" refers to one or more
chromosomal DNA molecules occurring naturally in the nucleus of a
human cell, or a portion of the chromosomal DNA molecules.
[0034] The term "genomic profile" refers to a set of information
about an individual's genes, such as the presence or absence of
specific SNPs or mutations. Genomic profiles include the genotypes
of individuals. Genomic profiles may also be substantially the
complete genomic sequence of an individual. In some embodiments,
the genomic profile may be at least 60%, 80%, or 95% of the
complete genomic sequence of an individual. The genomic profile may
be approximately 100% of the complete genomic sequence of an
individual. In reference to a genomic profile, "a portion thereof"
refers to the genomic profile of a subset of the genomic profile of
an entire genome.
[0035] The term "genotype" refers to the specific genetic makeup of
an individual's DNA. The genotype may include the genetic variants
and markers of an individual. Genetic markers and variants may
include nucleotide repeats, nucleotide insertions, nucleotide
deletions, chromosomal translocations, chromosomal duplications, or
copy number variations. Copy number variation may include
microsatellite repeats, nucleotide repeats, centromeric repeats, or
telomeric repeats. The genotypes may also be SNPs, haplotypes, or
diplotypes. A haplotype may refer to a locus or an allele. A
haplotype is also referred to as a set of single nucleotide
polymorphisms (SNPs) on a single chromatid that are statistically
associated. A diplotype is a set of haplotypes.
[0036] The term single nucleotide polymorphism or "SNP" refers to a
particular locus on a chromosome which exhibits variability such as
at least one percent (1%) with respect to the identity of the
nitrogenous base present at such locus within the human population.
For example, where one individual might have adenosine (A) at a
particular nucleotide position of a given gene, another might have
cytosine (C), guanine (G), or thymine (T) at this position, such
that there is a SNP at that particular position.
[0037] As used herein, the terminology "SNP genomic profile" refers
to the base content of a given individual's DNA at SNP sites
throughout the individual's entire genomic DNA sequence. A "SNP
profile" can refer to an entire genomic profile, or may refer to a
portion thereof, such as a more localized SNP profile which can be
associated with a particular gene or set of genes.
[0038] The term "phenotype" is used to describe a quantitative
trait or characteristic of an individual. Phenotypes include, but
are not limited to, medical and non-medical conditions. Medical
conditions include diseases and disorders. Phenotypes may also
include physical traits, such as hair color, physiological traits,
such as lung capacity, mental traits, such as memory retention,
emotional traits, such as ability to control anger, ethnicity, such
as ethnic background, ancestry, such as an individual's place of
origin, and age, such as age expectancy or age of onset of
different phenotypes. Phenotypes may also be monogenic, wherein it
is thought that one gene may be correlated with a phenotype, or
multigenic, wherein more than one gene is correlated with a
phenotype.
[0039] A "rule" is used to define the correlation between a
genotype and a phenotype. The rules may define the correlations by
a numerical value, for example by a percentage, risk factor, or
confidence score. A rule may incorporate the correlations of a
plurality of genotypes with a phenotype. A "rule set" comprises
more than one rule. A "new rule" may be a rule that indicates a
correlation between a genotype and a phenotype for which a rule
does not currently exist. A new rule may correlate an uncorrelated
genotype with a phenotype. A new rule may also correlate a genotype
that is already correlated with a phenotype to a phenotype it had
not been previously correlated to. A "new rule" may also be an
existing rule that is modified by other factors, including another
rule. An existing rule may be modified due to an individual's known
characteristics, such as ethnicity, ancestry, geography, gender,
age, family history, or other previously determined phenotypes.
[0040] Use of "genotype correlation" herein refers to the
statistical correlation between an individual's genotype, such as
presence of a certain mutation or mutations, and the likelihood of
being predisposed to a phenotype, such as a particular disease,
condition, physical state, and/or mental state. The frequency with
which a certain phenotype is observed in the presence of a specific
genotype determines the degree of genotype correlation or
likelihood of a particular phenotype. For example, as detailed
herein, SNPs giving rise to the apolipoprotein E4 isoform are
correlated with being predisposed to early onset Alzheimer's
disease. Genotype correlations may also refer to correlations
wherein there is not a predisposition to a phenotype, or a negative
correlation. The genotype correlations may also represent an
estimate of an individual to have a phenotype or be predisposed to
have a phenotype. The genotype correlation may be indicated by a
numerical value, such as a percentage, a relative risk factor, an
effects estimate, or confidence score.
[0041] The term "phenotype profile" refers to a collection of a
plurality of phenotypes correlated with a genotype or genotypes of
an individual. Phenotype profiles may include information generated
by applying one or more rules to a genomic profile, or information
about genotype correlations that are applied to a genomic profile.
Phenotype profiles may be generated by applying rules that
correlate a plurality of genotypes with a phenotype. The
probability or estimate may be expressed as a numerical value, such
as a percentage, a numerical risk factor or a numerical confidence
interval. The probability may also be expressed as high, moderate,
or low. The phenotype profiles may also indicate the presence or
absence of a phenotype or the risk of developing a phenotype. For
example, a phenotype profile may indicate the presence of blue
eyes, or a high risk of developing diabetes. The phenotype profiles
may also indicate a predicted prognosis, effectiveness of a
treatment, or response to a treatment of a medical condition.
[0042] As used herein, the term "on-line portal" refers to a source
of information which can be readily accessed by an individual
through use of a computer and internet website, telephone, or other
means that allow similar access to information. The on-line portal
may be a secure website. The website may provide links to other
secure and non-secure websites, for example links to a secure
website with the individual's phenotype profile, or to non-secure
websites such as a message board for individuals sharing a specific
phenotype.
[0043] The practice of the present invention may employ, unless
otherwise indicated, conventional techniques and descriptions of
molecular biology, cell biology, biochemistry, and immunology,
which are within the skill of the art. Such conventional techniques
include nucleic acid isolation, polymer array synthesis,
hybridization, ligation, and detection of hybridization using a
label. Specific illustrations of suitable techniques are
exemplified and referenced herein. However, other equivalent
conventional procedures can also be used. Other conventional
techniques and descriptions can be found in standard laboratory
manuals and texts such as Genome Analysis: A Laboratory Manual
Series (Vols. I-IV), PCR Primer: A Laboratory Manual, Molecular
Cloning: A Laboratory Manual (all from Cold Spring Harbor
Laboratory Press); Stryer, L. (1995) Biochemistry (4th Ed.)
Freeman, N.Y.; Gait, "Oligonucleotide Synthesis: A Practical
Approach" 1984, IRL Press, London, Nelson and Cox (2000);
Lehninger, Principles of Biochemistry 3rd Ed., W. H. Freeman Pub.,
New York, N.Y.; and Berg et al. (2002) Biochemistry, 5th Ed., W. H.
Freeman Pub., New York, N.Y., all of which are herein incorporated
in their entirety by reference for all purposes.
[0044] The methods of the present invention involve analysis of an
individual's genomic profile to provide the individual with
molecular information relating to a phenotype. As detailed herein,
the individual provides a genetic sample, from which a personal
genomic profile is generated. The data of the individual's genomic
profile is queried for genotype correlations by comparing the
profile against a database of established and validated human
genotype correlations. The database of established and validated
genotype correlations may be from peer-reviewed literature and
further judged by a committee of one or more experts in the field,
such as geneticists, epidemiologists, or statisticians, and
curated. In preferred embodiments, rules are made based on curated
genotype correlations and are applied to an individual's genomic
profile to generate a phenotype profile. Results of the analysis of
the individual's genomic profile, phenotype profile, along with
interpretation and supportive information, are provided to the
individual of the individual's health care manager, to empower
personalized choices for the individual's health care.
[0045] The method of the invention is detailed as in FIG. 1, where
an individual's genomic profile is first generated. An individual's
genomic profile will contain information about an individual's
genes based on genetic variations or markers. Genetic variations
are genotypes, which make up genomic profiles. Such genetic
variations or markers include, but are not limited to, single
nucleotide polymorphisms, single and/or multiple nucleotide
repeats, single and/or multiple nucleotide deletions,
microsatellite repeats (small numbers of nucleotide repeats with a
typical 5-1,000 repeat units), di-nucleotide repeats,
tri-nucleotide repeats, sequence rearrangements (including
translocation and duplication), copy number variations (both loss
and gains at specific loci), and the like. Other genetic variations
include chromosomal duplications and translocations as well as
centromeric and telomeric repeats.
[0046] Genotypes may also include haplotypes and diplotypes. In
some embodiments, genomic profiles may have at least 100,000,
300,000, 500,000, or 1,000,000 genotypes. In some embodiments, the
genomic profile may be substantially the complete genomic sequence
of an individual. In other embodiments, the genomic profile is at
least 60%, 80%, or 95% of the complete genomic sequence of an
individual. The genomic profile may be approximately 100% of the
complete genomic sequence of an individual. Genetic samples that
contain the targets include, but are not limited to, unamplified
genomic DNA or RNA samples or amplified DNA (or cDNA). The targets
may be particular regions of genomic DNA that contain genetic
markers of particular interest.
[0047] In step 102 of FIG. 1, a genetic sample of an individual is
isolated from a biological sample of an individual. Such biological
samples include, but are not limited to, blood, hair, skin, saliva,
semen, urine, fecal material, sweat, buccal, and various bodily
tissues. In some embodiments, tissues samples may be directly
collected by the individual, for example, a buccal sample may be
obtained by the individual taking a swab against the inside of
their cheek. Other samples such as saliva, semen, urine, fecal
material, or sweat, may also be supplied by the individual
themselves. Other biological samples may be taken by a health care
specialist, such as a phlebotomist, nurse or physician. For
example, blood samples may be withdrawn from an individual by a
nurse. Tissue biopsies may be performed by a health care
specialist, and kits are also available to health care specialists
to efficiently obtain samples. A small cylinder of skin may be
removed or a needle may be used to remove a small sample of tissue
or fluids.
[0048] In some embodiments, kits are provided to individuals with
sample collection containers for the individual's biological
sample. The kit may also provide instructions for an individual to
directly collect their own sample, such as how much hair, urine,
sweat, or saliva to provide. The kit may also contain instructions
for an individual to request tissue samples to be taken by a health
care specialist. The kit may include locations where samples may be
taken by a third party, for example kits may be provided to health
care facilities who in turn collect samples from individuals. The
kit may also provide return packaging for the sample to be sent to
a sample processing facility, where genetic material is isolated
from the biological sample in step 104.
[0049] A genetic sample of DNA or RNA may be isolated from a
biological sample according to any of several well-known
biochemical and molecular biological methods, see, e.g., Sambrook,
et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor
Laboratory, New York) (1989). There are also several commercially
available kits and reagents for isolating DNA or RNA from
biological samples, such as those available from DNA Genotek,
Gentra Systems, Qiagen, Ambion, and other suppliers. Buccal sample
kits are readily available commercially, such as the MasterAmp.TM.
Buccal Swab DNA extraction kit from Epicentre Biotechnologies, as
are kits for DNA extraction from blood samples such as
Extract-N-Amp.TM. from Sigma Aldrich. DNA from other tissues may be
obtained by digesting the tissue with proteases and heat,
centrifuging the sample, and using phenol-chloroform to extract the
unwanted materials, leaving the DNA in the aqueous phase. The DNA
can then be further isolated by ethanol precipitation.
[0050] In a preferred embodiment, genomic DNA is isolated from
saliva. For example, using DNA self collection kit technology
available from DNA Genotek, an individual collects a specimen of
saliva for clinical processing. The sample conveniently can be
stored and shipped at room temperature. After delivery of the
sample to an appropriate laboratory for processing, DNA is isolated
by heat denaturing and protease digesting the sample, typically
using reagents supplied by the collection kit supplier at
50.degree. C. for at least one hour. The sample is next
centrifuged, and the supernatant is ethanol precipitated. The DNA
pellet is suspended in a buffer appropriate for subsequent
analysis.
[0051] In another embodiment, RNA may be used as the genetic
sample. In particular, genetic variations that are expressed can be
identified from mRNA. The term "messenger RNA" or "mRNA" includes,
but is not limited to pre-mRNA transcript(s), transcript processing
intermediates, mature mRNA(s) ready for translation and transcripts
of the gene or genes, or nucleic acids derived from the MRNA
transcript(s). Transcript processing may include splicing, editing
and degradation. As used herein, a nucleic acid derived from an
mRNA transcript refers to a nucleic acid for whose synthesis the
mRNA transcript or a subsequence thereof has ultimately served as a
template. Thus, a cDNA reverse transcribed from an mRNA, a DNA
amplified from the cDNA, an RNA transcribed from the amplified DNA,
etc., are all derived from the MRNA transcript. RNA can be isolated
from any of several bodily tissues using methods known in the art,
such as isolation of RNA from unfractionated whole blood using the
PAXgene.TM. Blood RNA System available from PreAnalytiX. Typically,
mRNA will be used to reverse transcribe cDNA, which will then be
used or amplified for gene variation analysis.
[0052] Prior to genomic profile analysis, a genetic sample will
typically be amplified, either from DNA or cDNA reverse transcribed
from RNA. DNA can be amplified by a number of methods, many of
which employ PCR. See, for example, PCR Technology: Principles and
Applications for DNA Amplification (Ed. H. A. Erlich, Freeman
Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and
Applications (Eds. Innis, et al., Academic Press, San Diego,
Calif., 1990); Mattila et al., Nucleic Acids Res. 19, 4967 (1991);
Eckert et al., PCR Methods and Applications 1, 17 (1991); PCR (Eds.
McPherson et al., IRL Press, Oxford); and U.S. Pat. Nos. 4,683,202,
4,683,195, 4,800,159 4,965,188, and 5,333,675, and each of which is
incorporated herein by reference in their entireties for all
purposes.
[0053] Other suitable amplification methods include the ligase
chain reaction (LCR) (for example, Wu and Wallace, Genomics 4, 560
(1989), Landegren et al., Science 241, 1077 (1988) and Barringer et
al. Gene 89:117 (1990)), transcription amplification (Kwoh et al.,
Proc. Natl. Acad. Sci. USA 86:1173-1177 (1989) and WO88/10315),
self-sustained sequence replication (Guatelli et al., Proc. Nat.
Acad. Sci. USA, 87:1874-1878 (1990) and WO90/06995), selective
amplification of target polynucleotide sequences (U.S. Pat. No.
6,410,276), consensus sequence primed polymerase chain reaction
(CP--PCR) (U.S. Pat. No. 4,437,975), arbitrarily primed polymerase
chain reaction (AP--PCR) (U.S. Pat. Nos. 5,413,909, 5,861,245)
nucleic acid based sequence amplification (NABSA), rolling circle
amplification (RCA), multiple displacement amplification (MDA)
(U.S. Pat. Nos. 6,124,120 and 6,323,009) and circle-to-circle
amplification (C2CA) (Dahl et al. Proc. Natl. Acad. Sci
101:4548-4553 (2004)). (See, U.S. Pat. Nos. 5,409,818, 5,554,517,
and 6,063,603, each of which is incorporated herein by reference).
Other amplification methods that may be used are described in, U.S.
Pat. Nos. 5,242,794, 5,494,810, 5,409,818, 4,988,617, 6,063,603 and
5,554,517 and in U.S. Ser. No. 09/854,317, each of which is
incorporated herein by reference.
[0054] Generation of a genomic profile in step 106 is performed
using any of several methods. Several methods are known in the art
to identify genetic variations and include, but are not limited to,
DNA sequencing by any of several methodologies, PCR based methods,
fragment length polymorphism assays (restriction fragment length
polymorphism (RFLP), cleavage fragment length polymorphism (CFLP))
hybridization methods using an allele-specific oligonucleotide as a
template (e.g., TaqMan PCR method, the invader method, the DNA chip
method), methods using a primer extension reaction, mass
spectrometry (MALDI-TOF/MS method), and the like.
[0055] In one embodiment, a high density DNA array is used for SNP
identification and profile generation. Such arrays are commercially
available from Affymetrix and Illumina (see Affymetrix
GeneChip.RTM. 500K Assay Manual, Affymetrix, Santa Clara, Calif.
(incorporated by reference); Sentrix.RTM. humanHap650Y genotyping
beadchip, Illumina, San Diego, Calif.).
[0056] For example, a SNP profile can be generated by genotyping
more than 900,000 SNPs using the Affymetrix Genome Wide Human SNP
Array 6.0. Alternatively, more than 500,000 SNPs through
whole-genome sampling analysis may be determined by using the
Affymetrix GeneChip Human Mapping 500K Array Set. In these assays,
a subset of the human genome is amplified through a single primer
amplification reaction using restriction enzyme digested,
adaptor-ligated human genomic DNA. As shown in FIG. 2, the
concentration of the ligated DNA may then be determined. The
amplified DNA is then fragmented and the quality of the sample
determined prior to continuing with step 106. If the samples meet
the PCR and fragmentation standards, the sample is denatured,
labeled, and then hybridized to a microarray consisting of small
DNA probes at specific locations on a coated quartz surface. The
amount of label that hybridizes to each probe as a function of the
amplified DNA sequence is monitored, thereby yielding sequence
information and resultant SNP genotyping.
[0057] Use of the Affymetrix GeneChip 500K Assay is carried out
according to the manufacturer's directions. Briefly, isolated
genomic DNA is first digested with either a NspI or StyI
restriction endonuclease. The digested DNA is then ligated with a
NspI or StyI adaptor oligonucleotide that respectively anneals to
either the NspI or StyI restricted DNA. The adaptor-containing DNA
following ligation is then amplified by PCR to yield amplified DNA
fragments between about 200 and 1100 base pairs, as confirmed by
gel electrophoresis. PCR products that meet the amplification
standard are purified and quantified for fragmentation. The PCR
products are fragmented with DNase I for optimal DNA chip
hybridization. Following fragmentation, DNA fragments should be
less than 250 base pairs, and on average, about 180 base pairs, as
confirmed by gel electrophoresis. Samples that meet the
fragmentation standard are then labeled with a biotin compound
using terminal deoxynucleotidyl transferase. The labeled fragments
are next denatured and then hybridized into a GeneChip 250K array.
Following hybridization, the array is stained prior to scanning in
a three step process consisting of a streptavidin phycoerythin
(SAPE) stain, followed by an antibody amplification step with a
biotinylated, anti-streptavidin antibody (goat), and final stain
with streptavidin phycoerythin (SAPE). After labeling, the array is
covered with an array holding buffer and then scanned with a
scanner such as the Affymetrix GeneChip Scanner 3000.
[0058] Analysis of data following scanning of an Affymetrix
GeneChip Human Mapping 500K Array Set is performed according to the
manufacturer's guidelines, as shown in FIG. 3. Briefly, acquisition
of raw data using GeneChip Operating Software (GCOS) occurs. Data
may also be aquired using Affymetrix GeneChip Command Console.TM..
The aquisition of raw data is followed by analysis with GeneChip
Genotyping Analysis Software (GTYPE). For purposes of the present
invention, samples with a GTYPE call rate of less than 80% are
excluded. Samples are then examined with BRLMM and/or SNiPer
algorithm analyses. Samples with a BRLMM call rate of less than 95%
or a SNiPer call rate of less than 98% are excluded. Finally, an
association analysis is performed, and samples with a SNiPer
quality index of less than 0.45 and/or a Hardy-Weinberg p-value of
less than 0.00001 are excluded.
[0059] As an alternative to or in addition to DNA microarray
analysis, genetic variations such as SNPs and mutations can be
detected by DNA sequencing. DNA sequencing may also be used to
sequence a substantial portion, or the entire, genomic sequence of
an individual. Traditionally, common DNA sequencing has been based
on polyacrylamide gel fractionation to resolve a population of
chain-terminated fragments (Sanger et al., Proc. Natl. Acad. Sci.
USA 74:5463-5467 (1977)). Alternative methods have been and
continue to be developed to increase the speed and ease of DNA
sequencing. For example, high throughput and single molecule
sequencing platforms are commercially available or under
development from 454 Life Sciences (Branford, Conn.) (Margulies et
al., Nature (2005) 437:376-380 (2005)); Solexa (Hayward, Calif.);
Helicos BioSciences Corporation (Cambridge, Mass.) (U.S.
application Ser. No. 11/167046, filed Jun. 23, 2005), and Li-Cor
Biosciences (Lincoln, Nebr.) (U.S. application Ser. No. 11/118031,
filed Apr. 29, 2005).
[0060] After an individual's genomic profile is generated in step
106, the profile is stored digitally in step 108, such profile may
be stored digitally in a secure manner. The genomic profile is
encoded in a computer readable format to be stored as part of a
data set and may be stored as a database, where the genomic profile
may be "banked", and can be accessed again later. The data set
comprises a plurality of data points, wherein each data point
relates to an individual. Each data point may have a plurality of
data elements. One data element is the unique identifier, used to
identify the individual's genomic profile. It may be a bar code.
Another data element is genotype information, such as the SNPs or
nucleotide sequence of the individual's genome. Data elements
corresponding to the genotype information may also be included in
the data point. For example, if the genotype information includes
SNPs identified by microarray analysis, other data elements may
include the microarray SNP identification number, the SNP rs
number, and the polymorphic nucleotide. Other data elements may be
chromosome position of the genotype information, quality metrics of
the data, raw data files, images of the data, and extracted
intensity scores.
[0061] The individual's specific factors such as physical data,
medical data, ethnicity, ancestry, geography, gender, age, family
history, known phenotypes, demographic data, exposure data,
lifestyle data, behavior data, and other known phenotypes may also
be incorporated as data elements. The specific factors may be
obtained from a questionnaire or from a health care manager of the
individual. Information from the "banked" profile can then be
accessed and utilized as desired. For example, in the initial
assessment of an individual's genotype correlations, the
individual's entire information (typically SNPs or other genomic
sequences across, or taken from an entire genome) will be analyzed
for genotype correlations. In subsequent analyses, either the
entire information can be accessed, or a portion thereof, from the
stored, or banked genomic profile, as desired or appropriate.
Comparison of Genomic Profile with Database of Genotype
Correlations.
[0062] In step 110, genotype correlations are obtained from
scientific literature. Genotype correlations for genetic variations
are determined from analysis of a population of individuals who
have been tested for the presence or absence of one or more
phenotypic traits of interest and for genotype profile. The alleles
of each genetic variation or polymorphism in the profile are then
reviewed to determine whether the presence or absence of a
particular allele is associated with a trait of interest.
Correlation can be performed by standard statistical methods and
statistically significant correlations between genetic variations
and phenotypic characteristics are noted. For example, it may be
determined that the presence of allele A1 at polymorphism A
correlates with heart disease. As a further example, it might be
found that the combined presence of allele A1 at polymorphism A and
allele B1 at polymorphism B correlates with increased risk of
cancer. The results of the analyses may be published in
peer-reviewed literature, validated by other research groups,
and/or analyzed by a committee of experts, such as geneticists,
statisticians, epidemiologists, and physicians, and may also be
curated.
[0063] In FIGS. 4, 5, and 6 are examples of correlations between
genotypes and phenotypes from which rules to be applied to genomic
profiles may be based. For example, in FIGS. 4A and B, each row
corresponds to a phenotype/locus/ethnicity, wherein FIGS. 4C
through I contains further information about the correlations for
each of these rows. As an example, in FIG. 4A, the "Short Phenotype
Name" of BC, as noted in FIG. 4M, an index for the names of the
short phenotypes, is an abbreviation for breast cancer. In row
BC_4, which is the generic name for the locus, the gene LSP1 is
correlated to breast cancer. The published or functional SNP
identified with this correlation is rs3817198, as shown in FIG. 4C,
with the published risk allele being C, the nonrisk allele being T.
The published SNP and alleles are identified through publications
such as seminal publications as in FIGS. 4E-G. In the example of
LSP1 in FIG. 4E, the seminal publication is Easton et al., Nature
447:713-720 (2007).
[0064] Alternatively, the correlations may be generated from the
stored genomic profiles. For example, individuals with stored
genomic profiles may also have known phenotype information stored
as well. Analysis of the stored genomic profiles and known
phenotypes may generate a genotype correlation. As an example, 250
individuals with stored genomic profiles also have stored
information that they have previously been diagnosed with diabetes.
Analysis of their genomic profiles is performed and compared to a
control group of individuals without diabetes. It is then
determined that the individuals previously diagnosed with diabetes
have a higher rate of having a particular genetic variant compared
to the control group, and a genotype correlation may be made
between that particular genetic variant and diabetes.
[0065] In step 112, rules are made based on the validated
correlations of genetic variants to particular phenotypes. Rules
may be generated based on the genotypes and phenotypes correlated
as listed in Table 1, for example. Rules based on correlations may
incorporate other factors such as gender (e.g. FIG. 4) or ethnicity
(FIGS. 4 and 5), to generate effects estimates, such as those in
FIGS. 4 and 5. Other measures resulting from rules may be estimated
relative risk increase such as in FIG. 6. The effects estimates and
estimated relative risk increase may be from the published
literature, or calculated from the published literature.
Alternatively, the rules may be based on correlations generated
from stored genomic profiles and previously known phenotypes.
[0066] In a preferred embodiment, the genetic variants will be
SNPs. While SNPs occur at a single site, individuals who carry a
particular SNP allele at one site often predictably carry specific
SNP alleles at other sites. A correlation of SNPs and an allele
predisposing an individual to disease or condition occurs through
linkage disequilibrium, in which the non-random association of
alleles at two or more loci occur more or less frequently in a
population than would be expected from random formation through
recombination.
[0067] Other genetic markers or variants, such as nucleotide
repeats or insertions, may also be in linkage disequilibrium with
genetic markers that have been shown to be associated with specific
phenotypes. For example, a nucleotide insertion is correlated with
a phenotype and a SNP is in linkage disequilibrium with the
nucleotide insertion. A rule is made based on the correlation
between the SNP and the phenotype. A rule based on the correlation
between the nucleotide insertion and the phenotype may also be
made. Either rules or both rules may be applied to a genomic
profile, as the presence of one SNP may give a certain risk factor,
the other may give another risk factor, and when combined may
increase the risk.
[0068] Through linkage disequilibrium, a disease predisposing
allele cosegregates with a particular allele of a SNP or a
combination of particular alleles of SNPs. A particular combination
of SNP alleles along a chromosome is termed a haplotype, and the
DNA region in which they occur in combination can be referred to as
a haplotype block. While a haplotype block can consist of one SNP,
typically a haplotype block represents a contiguous series of 2 or
more SNPs exhibiting low haplotype diversity across individuals and
with generally low recombination frequencies. An identification of
a haplotype can be made by identification of one or more SNPs that
lie in a haplotype block. Thus, a SNP profile typically can be used
to identify haplotype blocks without necessarily requiring
identification of all SNPs in a given haplotype block.
[0069] Genotype correlations between SNP haplotype patterns and
diseases, conditions or physical states are increasingly becoming
known. For a given disease, the haplotype patterns of a group of
people known to have the disease are compared to a group of people
without the disease. By analyzing many individuals, frequencies of
polymorphisms in a population can be determined, and in turn these
frequencies or genotypes can be associated with a particular
phenotype, such as a disease or a condition. Examples of known
SNP-disease correlations include polymorphisms in Complement Factor
H in age-related macular degeneration (Klein et al., Science:
308:385-389, (2005)) and a variant near the INSIG2 gene associated
with obesity (Herbert et al., Science: 312:279-283 (2006)). Other
known SNP correlations include polymorphisms in the 9p21 region
that includes CDKN2A and B, such as ) such as rs10757274,
rs2383206, rs13333040, rs2383207, and rs10116277 correlated to
myocardial infarction (Helgadottir et al., Science 316:1491-1493
(2007); McPherson et al., Science 316:1488-1491 (2007))
[0070] The SNPs may be functional or non-functional. For example, a
functional SNP has an effect on a cellular function, thereby
resulting in a phenotype, whereas a non-functional SNP is silent in
function, but may be in linkage disequilibrium with a functional
SNP. The SNPs may also be synonymous or non-synonymous. SNPs that
are synonymous are SNPs in which the different forms lead to the
same polypeptide sequence, and are non-functional SNPs. If the SNPs
lead to different polypetides, the SNP is non-synonymous and may or
may not be functional. SNPs, or other genetic markers, used to
identify haplotypes in a diplotype, which is 2 or more haplotypes,
may also be used to correlate phenotypes associated with a
diplotype. Information about an individual's haplotypes,
diplotypes, and SNP profiles may be in the genomic profile of the
individual.
[0071] In preferred embodiments, for a rule to be generated based
on a genetic marker in linkage disequilibrium with another genetic
marker that is correlated with a phenotype, the genetic marker may
have a r.sup.2 or D' score, scores commonly used in the art to
determine linkage disequilibrium, of greater than 0.5. In preferred
embodiments, the score is greater than 0.6, 0.7, 0.8, 0.90, 0.95 or
0.99. As a result, in the present invention, the genetic marker
used to correlate a phenotype to an individual's genomic profile
may be the same as the functional or published SNP correlated to a
phenotype, or different. For example, using BC_4, the test SNP and
published SNP are the same, as are the test risk and nonrisk
alleles are the same as the published risk and nonrisk alleles
(FIGS. 4A and C). However, for BC_5, CASP8 and its correlation to
breast cancer, the test SNP is different from its functional or
published SNP, as are the test risk and nonrisk alleles to the
published risk and nonrisk alleles. The test and published alleles
are oriented relative to the plus strand of the genome, and from
these columns, it can be inferred the homozygous risk or nonrisk
genotype, which may generate a rule to be applied to the genomic
profile of individuals such as subscribers.
[0072] The test SNPs may be "DIRECT" or "TAG" SNPs (FIGS. 4E-G,
FIG. 5). Direct SNPs are the test SNPs that are the same as the
published or functional SNP, such as for BC_4. Direct SNPs may also
be used for FGFR2 correlation with breast cancer, using the SNP
rs1073640 in Europeans and Asians, where the minor allele is A and
the other allele is G (Easton et al., Nature 447:1087-1093 (2007)).
Another published or functional SNP for FGFR2 correlation to breast
cancer is rs1219648, also in Europeans and Asians (Hunter et al.,
Nat. Genet. 39:870-874 (2007)). Tag SNPs are where the test SNP is
different from that of the functional or published SNP, as in for
BC_5. Tag SNPs may also be used for other genetic variants such as
SNPs for CAMTA1 (rs4908449), 9p21 (rs10757274, rs2383206,
rs13333040, rs2383207, rs10116277), COL1A1 (rs1800012), FVL
(rs6025), HLA-DQA1 (rs4988889, rs2588331), eNOS (rs1799983), MTHFR
(rs1801133), and APC (rs28933380).
[0073] Databases of SNPs are publicly available from, for example,
the International HapMap Project (see www.hapmap.org, The
International HapMap Consortium, Nature 426:789-796 (2003), and The
International HapMap Consortium, Nature 437:1299-1320 (2005)), the
Human Gene Mutation Database (HGMD) public database (see
www.hgmd.org), and the Single Nucleotide Polymorphism database
(dbSNP) (see www.ncbi.nlm.nih.gov/SNP/). These databases provide
SNP haplotypes, or enable the determination of SNP haplotype
patterns. Accordingly, these SNP databases enable examination of
the genetic risk factors underlying a wide range of diseases and
conditions, such as cancer, inflammatory diseases, cardiovascular
diseases, neurodegenerative diseases, and infectious diseases. The
diseases or conditions may be actionable, in which treatments and
therapies currently exist. Treatments may include prophylactic
treatments as well as treatments that ameliorate symptoms and
conditions, including lifestyle changes.
[0074] Many other phenotypes such as physical traits, physiological
traits, mental traits, emotional traits, ethnicity, ancestry, and
age may also be examined. Physical traits may include height, hair
color, eye color, body, or traits such as stamina, endurance, and
agility. Mental traits may include intelligence, memory
performance, or learning performance. Ethnicity and ancestry may
include identification of ancestors or ethnicity, or where an
individual's ancestors originated from. The age may be a
determination of an individual's real age, or the age in which an
individual's genetics places them in relation to the general
population. For example, an individual's real age is 38 years of
age, however their genetics may determine their memory capacity or
physical well-being may be of the average 28 year old. Another age
trait may be a projected longevity for an individual.
[0075] Other phenotypes may also include non-medical conditions,
such as "fun" phenotypes. These phenotypes may include comparisons
to well known individuals, such as foreign dignitaries,
politicians, celebrities, inventors, athletes, musicians, artists,
business people, and infamous individuals, such as convicts. Other
"fun" phenotypes may include comparisons to other organisms, such
as bacteria, insects, plants, or non-human animals. For example, an
individual may be interested to see how their genomic profile
compares to that of their pet dog, or to a former president.
[0076] At step 114, the rules are applied to the stored genomic
profile to generate a phenotype profile of step 116. For example,
information in FIGS. 4, 5, or 6 may form the basis of rules, or
tests, to apply to an individual's genomic profile. The rules may
encompass the information on test SNP and alleles, and the effect
estimates of FIG. 4, where the UNITS for effect estimate is the
units of the effect estimate, such as OR, or odds-ratio (95%
confidence interval) or mean. The effects estimate may be a
genotypic risk (FIGS. 4C-G) in preferred embodiments, such as the
risk for homozygotes (homoz or RR), risk heterozygotes (heteroz or
RN), and nonrisk homozygotes (homoz or NN). In other embodiments,
the effect estimate may be carrier risk, which is RR or RN vs NN.
In yet other embodiments, the effect estimate may be based on the
allele, an allelic risk such as R vs. N. There may also be two
locus (FIG. 4J) or three locus (FIG. 4K) genotypic effect estimate
(e.g. RRRR, RRNN, etc for the 9 possible genotype combinations for
a two locus effect estimate). The test SNP frequency in the public
HapMap is also noted in FIGS. 4H and I.
[0077] The phenotype profile of an individual may comprise a number
of phenotypes. In particular, the assessment of a patient's risk of
disease or other conditions such as likely drug response including
metabolism, efficacy and/or safety, by the methods of the present
invention allows for prognostic or diagnostic analysis of
susceptibility to multiple, unrelated diseases and conditions,
whether in symptomatic, presymptomatic or asymptomatic individuals,
including carriers of one or more disease/condition predisposing
alleles. Accordingly, these methods provide for general assessment
of an individual's susceptibility to disease or condition without
any preconceived notion of testing for a specific disease or
condition. For example, the methods of the present invention allow
for assessment of an individual's susceptibility to any of the
several conditions listed in Tables 1, FIG. 4, 5, or 6, based on
the individual's genomic profile. The assessment preferably
provides information for 2 or more of these conditions, and more
preferably, 3, 4, 5, 10, 20, 50, 100 or even more of these
conditions. In preferred embodiments, the phenotype profile results
from the application of at least 20 rules to the genomic profile of
an individual. In other embodiments, at least 50 rules are applied
to the genomic profile of an individual. A single rule for a
phenotype may be applied for monogenic phenotypes. More than one
rule may also be applied for a single phenotype, such as a
multigenic phenotype or a monogenic phenotype wherein multiple
genetic variants within a single gene affects the probability of
having the phenotype.
[0078] Following an initial screening of an individual patient's
genomic profile, updates of an individual's genotype correlations
are made (or are available) through comparisons to additional
nucleotide variants, such as SNPs, when such additional nucleotide
variants become known. For example, step 110 may be performed
periodically, for example, daily, weekly, or monthly by one or more
people of ordinary skill in the field of genetics, who scan
scientific literature for new genotype correlations. The new
genotype correlations may then be further validated by a committee
of one or more experts in the field. Step 112 may then also be
periodically updated with new rules based on the new validated
correlations.
[0079] The new rule may encompass a genotype or phenotype without
an existing rule. For example, a genotype not correlated with any
phenotype is discovered to correlate with a new or existing
phenotype. A new rule may also be for a correlation between a
phenotype for which no genotype has previously been correlated to.
New rules may also be determined for genotypes and phenotypes that
have existing rules. For example, a rule based on the correlation
between genotype A and phenotype A exists. New research reveals
genotype B correlates with phenotype A, and a new rule based on
this correlation is made. Another example is phenotype B is
discovered to be associated with genotype A, and thus a new rule
may be made.
[0080] Rules may also be made on discoveries based on known
correlations but not initially identified in published scientific
literature. For example, it may be reported genotype C is
correlated with phenotype C. Another publication reports genotype D
is correlated with phenotype D. Phenotype C and D are related
symptoms, for example phenotype C may be shortness of breath, and
phenotype D is small lung capacity. A correlation between genotype
C and phenotype D, or genotype D with phenotype C, may be
discovered and validated through statistical means with existing
stored genomic profiles of individuals with genotypes C and D, and
phenotypes C and D, or by further research. A new rule may then be
generated based on the newly discovered and validated correlation.
In another embodiment, stored genomic profiles of a number of
individuals with a specific or related phenotype may be studied to
determine a genotype common to the individuals, and a correlation
may be determined. A new rule may be generated based on this
correlation.
[0081] Rules may also be made to modify existing rules. For
example, correlations between genotypes and phenotypes may be
partly determined by a known individual characteristic, such as
ethnicity, ancestry, geography, gender, age, family history, or any
other known phenotypes of the individual. Rules based on these
known individual characteristics may be made and incorporated into
an existing rule, to provide a modified rule. The choice of
modified rule to be applied will be dependent on the specific
individual factor of an individual. For example, a rule may be
based on the probability an individual who has phenotype E is 35%
when the individual has genotype E. However, if an individual is of
a particular ethnicity, the probability is 5%. A new rule may be
generated based on this result and applied to individuals with that
particular ethnicity. Alternatively, the existing rule with a
determination of 35% may be applied, and then another rule based on
ethnicity for that phenotype is applied. The rules based on known
individual characteristics may be determined from scientific
literature or determined based on studies of stored genomic
profiles. New rules may be added and applied to genomic profiles in
step 114, as the new rules are developed, or they may be applied
periodically, such as at least once a year.
[0082] Information of an individual's risk of disease can also be
expanded as technology advances allow for finer resolution SNP
genomic profiles. As indicated above, an initial SNP genomic
profile readily can be generated using microarray technology for
scanning of 500,000 SNPs. Given the nature of haplotype blocks,
this number allows for a representative profile of all SNPs in an
individual's genome. Nonetheless, there are approximately 10
million SNPs estimated to occur commonly in the human genome (the
International HapMap Project; www.hapmap.org). As technological
advances allow for practical, cost-efficient resolution of SNPs at
a finer level of detail, such as microarrays of 1,000,000,
1,500,000, 2,000,000, 3,000,000, or more SNPs, or whole genomic
sequencing, more detailed SNP genomic profiles can be generated.
Likewise, cost-efficient analysis of finer SNP genomic profiles and
updates to the master database of SNP-disease correlations will be
enabled by advances in computational analytical methodology.
[0083] After generation of phenotype profile at step 116, a
subscriber or their health care manager may access their genomic or
phenotype profiles via an on-line portal or website as in step 118.
Reports containing phenotype profiles and other information related
to the phenotype and genomic profiles may also be provided to the
subscriber or their health care manager, as in steps 120 and 122.
The reports may be printed, saved on the subscriber's computer, or
viewed on-line.
[0084] A sample on-line report is shown in FIG. 7. The subscriber
may choose to display a single phenotype, or more than one
phenotype. The subscriber may also have different viewing options,
for example, as shown in FIG. 7, a "Quick View" option. The
phenotype may be a medical condition and different treatments and
symptoms in the quick report may link to other web pages that
contain further information about the treatment. For example, by
clicking on a drug, it will lead to website that contains
information about dosages, costs, side effects, and effectiveness.
It may also compare the drug to other treatments. The website may
also contain a link leading to the drug manufacturer's website.
Another link may provide an option for the subscriber to have a
pharmacogenomic profile generated, which would include information
such as their likely response to the drug based on their genomic
profile. Links to alternatives to the drug may also be provided,
such as preventative action such as fitness and weight loss, and
links to diet supplements, diet plans, and to nearby health clubs
may also be provided.
[0085] The on-line report may also provide links to schedule
in-person physician or genetic counseling appointments or to access
an on-line genetic counselor or physician, providing the
opportunity for a subscriber to ask for more information regarding
their phenotype profile. Links to on-line genetic counseling and
physician questions may also be provided on the on-line report.
[0086] Reports may also be viewed in other formats such as a
comprehensive view for a single phenotype, wherein more detail for
each category is provided. For example, there may be more detailed
statistics about the likelihood of the subscriber developing the
phenotype, more information about the typical symptoms or
phenotypes, such as sample symptoms for a medical condition, or the
range of a physical non-medical condition such as height, or more
information about the gene and genetic variant, such as the
population incidence, for example in the world, or in different
countries, or in different age ranges or genders. In another
embodiment, the report may be of a "fun" phenotype, such as the
similarity of an individual's genomic profile to that of a famous
individual, such as Albert Einstein. The report may display a
percentage similarity between the individual's genomic profile to
that of Einstein's, and may further display a predicted IQ of
Einstein and that of the individual's. Further information may
include how the genomic profile of the general population and their
IQ compares to that of the individual's and Einstein's.
[0087] In another embodiment, the report may display all phenotypes
that have been correlated to the subscriber's genomic profile. In
other embodiments, the report may display only the phenotypes that
are positively correlated with an individual's genomic profile. In
other formats, the individual may choose to display certain
subgroups of phenotypes, such as only medical phenotypes, or only
actionable medical phenotypes. For example, actionable phenotypes
and their correlated genotypes, may include Crohn's disease
(correlated with IL23R and CARD 15), Type 1 diabetes (correlated
with HLA-DR/DQ), lupus (correlated HLA-DRB1), psoriasis (HLA-C),
multiple sclerosis (HLA-DQA1), Graves disease (HLA-DRB1),
rheumatoid arthritis (HLA-DRB1), Type 2 diabetes (TCF7L2), breast
cancer (BRCA2), colon cancer (APC), episodic memory (KIBRA), and
osteoporosis (COL1A1). The individual may also choose to display
subcategories of phenotypes in their report, such as only
inflammatory diseases for medical conditions, or only physical
traits for non-medical conditions.
[0088] Information submitted by and conveyed to an individual may
be secure and confidential, and access to such information may be
controlled by the individual. Information derived from the complex
genomic profile may be supplied to the individual as regulatory
agency approved, understandable, medically relevant and/or high
impact data. Information may also be of general interest, and not
medically relevant. Information can be securely conveyed to the
individual by several means including, but not restricted to, a
portal interface and/or mailing. More preferably, information is
securely (if so elected by the individual) provided to the
individual by a portal interface, to which the individual has
secure and confidential access. Such an interface is preferably
provided by on-line, internet website access, or in the
alternative, telephone or other means that allow private, secure,
and readily available access. The genomic profiles, phenotype
profiles, and reports are provided to an individual or their health
care manager by transmission of the data over a network.
[0089] Accordingly, FIG. 8 is a block diagram showing a
representative example logic device through which a phenotype
profile and report may be generated. FIG. 8 shows a computer system
(or digital device) 800 to receive and store genomic profiles,
analyze genotype correlations, generate rules based on the analysis
of genotype correlations, apply the rules to the genomic profiles,
and produce a phenotype profile and report. The computer system 800
may be understood as a logical apparatus that can read instructions
from media 811 and/or network port 805, which can optionally be
connected to server 809 having fixed media 812. The system shown in
FIG. 5 includes CPU 801, disk drives 803, optional input devices
such as keyboard 815 and/or mouse 816 and optional monitor 807.
Data communication can be achieved through the indicated
communication medium to a server 809 at a local or a remote
location. The communication medium can include any means of
transmitting and/or receiving data. For example, the communication
medium can be a network connection, a wireless connection or an
internet connection. Such a connection can provide for
communication over the World Wide Web. It is envisioned that data
relating to the present invention can be transmitted over such
networks or connections for reception and/or review by a party 822.
The receiving party 822 can be but is not limited to an individual,
a subscriber, a health care provider or a health care manager. In
one embodiment, a computer-readable medium includes a medium
suitable for transmission of a result of an analysis of a
biological sample or a genotype correlation. The medium can include
a result regarding a phenotype profile of an individual subject,
wherein such a result is derived using the methods described
herein.
[0090] A personal portal will preferably serve as the primary
interface with an individual for receiving and evaluating genomic
data. A portal will enable individuals to track the progress of
their sample from collection through testing and results. Through
portal access, individuals are introduced to relative risks for
common genetic disorders based on their genomic profile. The
subscriber may choose which rules to apply to their genomic profile
through the portal.
[0091] In one embodiment, one or more web pages will have a list of
phenotypes and next to each phenotype a box in which a subscriber
may select to include in their phenotype profile. The phenotypes
may be linked to information on the phenotype, to help the
subscriber make an informed choice about the phenotype they want
included in their phenotype profile. The webpage may also have
phenotypes organized by disease groups, for example as actionable
diseases or not. For example, a subscriber may choose actionable
phenotypes only, such as HLA-DQA1 and celiac disease. The
subscriber may also choose to display pre or post symptomatic
treatments for the phenotypes. For example, the individual may
choose actionable phenotypes with pre-symptomatic treatments
(outside of increased screening), for celiac disease, a
pre-symptomatic treatment of gluten free diet. Another example may
be Alzheimer's, the pre-symptomatic treatment of statins, exercise,
vitamins, and mental activity. Thrombosis is another example, with
a pre-symptomatic treatment of avoid oral contraceptives and avoid
sitting still for long periods of time. An example of a phenotype
with an approved post symptomatic treatment is wet AMD, correlated
with CFH, wherein individuals may obtain laser treatment for their
condition.
[0092] The phenotypes may also be organized by type or class of
disease or conditions, for example neurological, cardiovascular,
endocrine, immunological, and so forth. Phenotypes may also be
grouped as medical and non-medical phenotypes. Other groupings of
phenotypes on the webpage may be by physical traits, physiological
traits, mental traits, or emotional traits. The webpage may further
provide a section in which a group of phenotypes are chosen by
selection of one box. For example, a selection for all phenotypes,
only medically relevant phenotypes, only non-medically relevant
phenotypes, only actionable phenotypes, only non-actionable
phenotypes, different disease group, or "fun" phenotypes. "Fun"
phenotypes may include comparisons to celebrities or other famous
individuals, or to other animals or even other organisms. A list of
genomic profiles available for comparison may also be provided on
the webpage for selection by the subscriber to compare to the
subscriber's genomic profile.
[0093] The on-line portal may also provide a search engine, to help
the subscriber navigate the portal, search for a specific
phenotype, or search for specific terms or information revealed by
their phenotype profile or report. Links to access partner services
and product offerings may also be provided by the portal.
Additional links to support groups, message boards, and chat rooms
for individuals with a common or similar phenotype may also be
provided. The on-line portal may also provide links to other sites
with more information on the phenotypes in a subscriber's phenotype
profile. The on-line portal may also provide a service to allow
subscribers to share their phenotype profile and reports with
friends, families, or health care managers. Subscribers may choose
which phenotypes to show in the phenotype profile they want shared
with their friends, families, or health care managers.
[0094] The phenotype profiles and reports provide a personalized
genotype correlation to an individual. The genotype correlations
provided to an individual can be used in determining personal
health care and lifestyle choices. If a strong correlation is found
between a genetic variant and a disease for which treatment is
available, detection of the genetic variant may assist in deciding
to begin treatment of the disease and/or monitoring of the
individual. In the case where a statistically significant
correlation exists but is not regarded as a strong correlation, an
individual can review the information with a personal physician and
decide an appropriate, beneficial course of action. Potential
courses of action that could be beneficial to an individual in view
of a particular genotype correlation include administration of
therapeutic treatment, monitoring for potential need of treatment
or effects of treatment, or making life-style changes in diet,
exercise, and other personal habits/activities. For example, an
actionable phenotype such as celiac disease may have a
pre-symptomatic treatment of a gluten-free diet. Likewise, genotype
correlation information could be applied through pharmacogenomics
to predict the likely response an individual would have to
treatment with a particular drug or regimen of drugs, such as the
likely efficacy or safety of a particular drug treatment.
[0095] Subscribers may choose to provide the genomic and phenotype
profiles to their health care managers, such as a physician or
genetic counselor. The genomic and phenotype profiles may be
directly accessed by the healthcare manager, by the subscriber
printing out a copy to be given to the healthcare manager, or have
it directly sent to the healthcare manager through the on-line
portal, such as through a link on the on-line report.
[0096] Delivery of this pertinent information will empower patients
to act in concert with their physician. In particular, discussions
between patients and their physicians can be empowered through an
individual's portal and links to medical information, and the
ability to tie patient's genomic information into their medical
records. Medical information may include prevention and wellness
information. The information provided to the individual patient by
the present invention will enable patients to make informed choices
for their health care. In this manner, patients will be able to
make choices that may help them avoid and/or delay diseases that
their individual genomic profile (inherited DNA) makes more likely.
In addition, patients will be able to employ a treatment regime
that personally fits their specific medical needs. Individuals also
will have the ability to access their genotype data should they
develop an illness and need this information to help their
physician form a therapeutic strategy.
[0097] Genotype correlation information could also be used in
cooperation with genetic counseling to advise couples considering
reproduction, and potential genetic concerns to the mother, father
and/or child. Genetic counselors may provide information and
support to subscribers with phenotype profiles that display an
increased risk for specific conditions or diseases. They may
interpret information about the disorder, analyze inheritance
patterns and risks of recurrence, and review available options with
the subscriber. Genetic counselors may also provide supportive
counseling refer subscribers to community or state support
services.
[0098] An individual's portal will also facilitate delivery of
additional information beyond an initial screening. Individuals
will be informed about new scientific discoveries that relate to
their personal genetic profile, such as information on new
treatments or prevention strategies for their current or potential
conditions. The new discoveries may also be delivered to their
healthcare managers. In preferred embodiments, the subscribers, or
their healthcare providers are informed of new genotype
correlations and new research about the phenotypes in the
subscriber's phenotype profiles, by e-mail. In other embodiments,
e-mails of "fun" phenotypes are sent to subscribers, for example,
an e-mail may inform them that their genomic profile is 77%
identical to that of Abraham Lincoln and that further information
is available via an on-line portal.
[0099] The present invention also provides a system of computer
code for generating new rules, modifying rules, combining rules,
periodically updating the rule set with new rules, maintaining a
database of genomic profile securely, applying the rules to the
genomic profiles to determine phenotype profiles, and for
generating reports. Computer code for notifying subscribers of new
or revised correlations new or revised rules, and new or revised
reports, for example with new prevention and wellness information,
information about new therapies in development, or new treatments
available.
Business Method
[0100] The present invention provides a business method of
assessing an individual's genotype correlations based on comparison
of the patient's genome profile against a clinically-derived
database of established, medically relevant nucleotide variants.
The present invention further provides a business method for using
the stored genomic profile of the individual for assessing new
correlations that were not initially known, to generate updated
phenotype profiles for an individual, without the requirement of
the individual submitting another biological sample. A flow chart
illustrating the business method is in FIG. 9.
[0101] A revenue stream for the subject business method is
generated in part at step 101, when an individual initially
requests and purchases a personalized genomic profile for genotype
correlations for a multitude of common human diseases, conditions,
and physical states. A request and purchase can be made through any
number of sources, including but not limited to, an on-line web
portal, an on-line health service, and an individual's personal
physician or similar source of personal medical attention. In an
alternative embodiment, the genomic profile may be provided free,
and the revenue stream is generated at a later step, such as step
103.
[0102] A subscriber, or customer, makes a request for purchase of a
phenotype profile. In response to a request and purchase, a
customer is provided a collection kit for a biological sample used
for genetic sample isolation at step 103. When a request is made
on-line, by telephone, or other source in which a collection kit is
not readily physically available to the customer, a collection kit
is provided by expedited delivery, such as courier service that
provides same-day or overnight delivery. Included in the collection
kit is a container for a sample, as well as packaging materials for
expedited delivery of the sample to a laboratory for genomic
profile generation. The kit may also include instructions for
sending the sample to the sample processing facility, or
laboratory, and instructions for accessing their genomic profile
and phenotype profile, which may occur through an on-line
portal.
[0103] As detailed above, genomic DNA can be obtained from any of a
number of types of biological samples. Preferably, genomic DNA is
isolated from saliva, using a commercially available collection kit
such as that available from DNA Genotek. Use of saliva and such a
kit allows for a non-invasive sample collection, as the customer
conveniently provides a saliva sample in a container from a
collection kit and then seals the container. In addition, a saliva
sample can be stored and shipped at room temperature.
[0104] After depositing a biological sample into a collection or
specimen container, a customer will deliver the sample to a
laboratory for processing at step 105. Typically, the customer may
use packaging materials provided in the collection kit to
deliver/send the sample to a laboratory by expedited delivery, such
as same-day or overnight courier service.
[0105] The laboratory that processes the sample and generates the
genomic profile may adhere to appropriate governmental agency
guidelines and requirements. For example, in the United States, a
processing laboratory may be regulated by one or more federal
agencies such as the Food and Drug Administration (FDA) or the
Centers for Medicare and Medicaid Services (CMS), and/or one or
more state agencies. In the United States, a clinical laboratory
may be accredited or approved under the Clinical Laboratory
Improvement Amendments of 1988 (CLIA).
[0106] At step 107, the laboratory processes the sample as
previously described to isolate the genetic sample of DNA or RNA.
Analysis of the isolated genetic sample and generation of a genomic
profile is then performed at step 109. Preferably, a genomic SNP
profile is generated. As described above, several methodologies may
be used to generate a SNP profile. Preferably, a high density
array, such as the commercially available platforms from Affymetrix
or Illumina, is used for SNP identification and profile generation.
For example, a SNP profile may be generated using an Affymetrix
GeneChip assay, as described above in more detail. As technology
evolves, there may be other technology vendors who can generate
high density SNP profiles. In another embodiment, a genomic profile
for a subscriber will be the genomic sequence of the
subscriber.
[0107] Following generation of an individual's genomic profile, the
genotype data is preferably encrypted, imported at step 111, and
deposited into a secure database or vault at step 113, where the
information is stored for future reference. The genomic profile and
related information may be confidential, with access to this
proprietary information and the genomic profile limited as directed
by the individual and/or his or her personal physician. Others,
such as family and the genetic counselor of the individual may also
be permitted access by the subscriber.
[0108] The database or vault may be located on-site with the
processing laboratory. Alternatively, the database may be located
at a separate location. In this scenario, the genomic profile data
generated by the processing lab can be imported at step 111 to a
separate facility that contains the database.
[0109] After an individual's genomic profile is generated, the
individual's genetic variations are then compared against a
clinically-derived database of established, medically relevant
genetic variants in step 115. Alternatively, the genotype
correlations may not be medically relevant but still incorporated
into the database of genotype correlations, for example, physical
traits such as eye color, or "fun" phenotypes such as genomic
profile similarity to a celebrity.
[0110] The medically relevant SNPs may have been established
through the scientific literature and related sources. The non-SNP
genetic variants may also be established to be correlated with
phenotypes. Generally, the correlation of SNPs to a given disease
is established by comparing the haplotype patterns of a group of
people known to have the disease to a group of people without the
disease. By analyzing many individuals, frequencies of
polymorphisms in a population can be determined, and in turn these
genotype frequencies can be associated with a particular phenotype,
such as a disease or a condition. Alternatively, the phenotype may
be a non-medical condition.
[0111] The relevant SNPs and non-SNP genetic variants may also be
determined through analysis of the stored genomic profiles of
individuals rather than determined by available published
literature. Individuals with stored genomic profiles may disclose
phenotypes that have previously been determined. Analysis of the
genotypes and disclosed phenotypes of the individuals may be
compared to those without the phenotypes to determine a correlation
that may then be applied to other genomic profiles. Individuals
that have their genomic profiles determined may fill out
questionnaires about phenotypes that have previously been
determined. Questionnaires may contain questions about medical and
non-medical conditions, such as diseases previously diagnosed,
family history of medical conditions, lifestyle, physical traits,
mental traits, age, social life, environment and the like.
[0112] In one embodiment, an individual may have their genomic
profile determined free of charge if they fill out a questionnaire.
In some embodiments, the questionnaires are to be filled out
periodically by the individuals in order to have free access to
their phenotype profile and reports. In other embodiments, the
individuals that fill out the questionnaires may be entitled to a
subscription upgrade, such that they have more access than their
previous subscription level, or they may purchase or renew a
subscription at a reduced cost.
[0113] All information deposited in the database of medically
relevant genetic variants at step 121 is first approved by a
research/clinical advisory board for scientific accuracy and
importance, coupled with review and oversight by an appropriate
governmental agency if warranted at step 119. For example, in the
United States, the FDA may provide oversight through approval of
algorithms used for validation of genetic variant (typically SNP,
transcript level, or mutation) correlative data. At step 123,
scientific literature and other relevant sources are monitored for
additional genetic variant-disease or condition correlations, and
following validation of their accuracy and importance, along with
governmental agency review and approval, these additional genotype
correlations are added to the master database at step 125.
[0114] The database of approved, validated medically-relevant
genetic variants, coupled with a genome-wide individual profile,
will advantageously allow genetic risk-assessment to be performed
for a large number of diseases or conditions. Following compilation
of an individual's genomic profile, individual genotype
correlations can be determined through comparison of the
individual's nucleotide (genetic) variants or markers with a
database of human nucleotide variants that have been correlated to
a particular phenotype, such as a disease, condition, or physical
state. Through comparison of an individual's genomic profile to the
master database of genotype correlations, the individual can be
informed whether they are found to be positive or negative for a
genetic risk factor, and to what degree. An individual will receive
relative risk and/or predisposition data on a wide range of
scientifically validated disease states (e.g., Alzheimer's,
cardiovascular disease, blood clotting). For example, genotype
correlations in Table 1 may be included. In addition, SNP disease
correlations in the database may include, but are not limited to,
those correlations shown in FIG. 4. Other correlations from FIGS. 5
and 6 may also be included. The subject business method therefore
provides analysis of risk to a multitude of diseases and conditions
without any preconceived notion of what those diseases and
conditions might entail.
[0115] In other embodiments, the genotype correlations that are
coupled to the genome wide individual profile are non-medically
relevant phenotypes, such as "fun" phenotypes or physical traits
such as hair color. In preferred embodiments, a rule or rule set is
applied to the genomic profile or SNP profile of an individual, as
described above. Application of the rules to a genomic profile
generates a phenotype profile for the individual.
[0116] Accordingly, the master database of human genotype
correlations is expanded with additional genotype correlations as
new correlations become discovered and validated. An update can be
made by accessing pertinent information from the individual's
genomic profile stored in a database as desired or appropriate. For
example, a new genotype correlation that becomes known may be based
on a particular gene variant. Determination of whether an
individual may be susceptible to that new genotype correlation can
then be made by retrieving and comparing just that gene portion of
the individual's entire genomic profile.
[0117] The results of the genomic query preferably are analyzed and
interpreted so as to be presented to the individual in an
understandable format. At step 117, the results of an initial
screening are then provided to the patient in a secure,
confidential form, either by mailing or through an on-line portal
interface, as detailed above.
[0118] The report may contain the phenotype profile as well as
genomic information about the phenotypes in the phenotype profile,
for example basic genetics about the genes involved or the
statistics of the genetic variants in different populations. Other
information based on the phenotype profile that may be included in
the report are prevention strategies, wellness information,
therapies, symptom awareness, early detection schemes, intervention
schemes, and refined identification and sub-classification of the
phenotypes. Following an initial screening of an individual's
genomic profile, controlled, moderated updates are or can be
made.
[0119] Updates of an individual's genomic profile are made or are
available in conjunction with updates to the master database as new
genotype correlations emerge and are both validated and approved.
New rules based on the new genotype correlations may be applied to
the initial genomic profile to provide updated phenotype profiles.
An updated genotype correlation profile can be generated by
comparing the relevant portion of the individual's genomic profile
to a new genotype correlation at step 127. For example, if a new
genotype correlation is found based on variation in a particular
gene, then that gene portion of the individual's genomic profile
can be analyzed for the new genotype correlation. In such a case,
one or more new rules may be applied to generate an updated
phenotype profile, rather than an entire rule set with rules that
had already been applied. The results of the individual's updated
genotype correlations are provided in a secure manner at step
129.
[0120] Initial and updated phenotype profiles may be a service
provided to subscribers or customers. Varying levels of
subscriptions to genomic profile analysis and combinations thereof
can be provided. Likewise, subscription levels can vary to provide
individuals choices of the amount of service they wish to receive
with their genotype correlations. Thus, the level of service
provided would vary with the level of service subscription
purchased by the individual.
[0121] An entry level subscription for a subscriber may include a
genomic profile and an initial phenotype profile. This may be a
basic subscription level. Within the basic subscription level may
be varying levels of service. For example, a particular
subscription level could provide references for genetic counseling,
physicians with particular expertise in treating or preventing a
particular disease, and other service options. Genetic counseling
may be obtained on-line or by telephone. In another embodiment, the
price of the subscription may depend on the number of phenotypes an
individual chooses for their phenotype profile. Another option may
be whether the subscriber chooses to access on-line genetic
counseling.
[0122] In another scenario, a subscription could provide for an
initial genome-wide, genotype correlation, with maintenance of the
individual's genomic profile in a database; such database may be
secure if so elected by the individual. Following this initial
analysis, subsequent analyses and additional results could be made
upon request and additional payment by the individual. This may be
a premium level of subscription.
[0123] In one embodiment of the subject business method, updates of
an individual's risks are performed and corresponding information
made available to individuals on a subscription basis. The updates
may be available to subscribers who purchase the premium level of
subscription. Subscription to genotype correlation analysis can
provide updates with a particular category or subset of new
genotype correlations according to an individual's preferences. For
example, an individual might only wish to learn of genotype
correlations for which there is a known course of treatment or
prevention. To aid an individual in deciding whether to have an
additional analysis performed, the individual can be provided with
information regarding additional genotype correlations that have
become available. Such information can be conveniently mailed or
e-mailed to a subscriber.
[0124] Within the premium subscription, there may be further levels
of service, such as those mentioned in the basic subscription.
Other subscription models may be provided within the premium level.
For example, the highest level may provide a subscriber to
unlimited updates and reports. The subscriber's profile may be
updated as new correlations and rules are determined. At this
level, subscribers may also permit access to unlimited number of
individuals, such as family members and health care managers. The
subscribers may also have unlimited access to on-line genetic
counselors and physicians.
[0125] The next level of subscription within the premium level may
provide more limited aspects, for example a limited number of
updates. The subscriber may have a limited number of updates for
their genomic profile within a subscription period, for example, 4
times a year. In another subscription level, the subscriber may
have their stored genomic profile updated once a week, once a
month, or once a year. In another embodiment, the subscriber may
only have a limited number of phenotypes they may choose to update
their genomic profile against.
[0126] A personal portal will also conveniently allow an individual
to maintain a subscription to risk or correlation updates and
information updates or alternatively, make requests for updated
risk assessment and information. As described above, varying
subscription levels could be provided to allow individuals choices
of various levels of genotype correlation results and updates and
may different subscription levels may be chosen by the subscriber
via their personal portal.
[0127] Any of these subscription options will contribute to the
revenue stream for the subject business method. The revenue stream
for the subject business method will also be added by the addition
of new customers and subscribers, wherein the new genomic profiles
are added to the database.
TABLE-US-00001 TABLE 1 Representative genes having genetic variants
correlated with a phenotype. Gene Phenotype A2M Alzheimer's Disease
ABCA1 cholesterol, HDL ABCB1 HIV ABCB1 epilepsy ABCB1 kidney
transplant complications ABCB1 digoxin, serum concentration ABCB1
Crohn's disease; ulcerative colitis ABCB1 Parkinson's disease ABCC8
Type 2 diabetes ABCC8 diabetes, type 2 ABO myocardial infarct ACADM
medium-chain acyl-CoA dehydrogenase deficiency ACDC Type 2 diabetes
ACE Type 2 diabetes ACE hypertension ACE Alzheimer's Disease ACE
myocardial infarction ACE cardiovascular ACE left ventricular
hypertrophy ACE coronary artery disease ACE atherosclerosis,
coronary ACE retinopathy, diabetic ACE systemic lupus erythematosus
ACE blood pressure, arterial ACE erectile dysfunction ACE Lupus ACE
polycystic kidney disease ACE stroke ACP1 Type 1 diabetes ACSM1
(LIP)c cholesterol levels ADAM33 asthma ADD1 hypertension ADD1
blood pressure, arterial ADH1B alcohol abuse ADH1C alcohol abuse
ADIPOQ Type 2 diabetes ADIPOQ obesity ADORA2A panic disorder ADRB1
hypertension ADRB1 heart failure ADRB2 asthma ADRB2 hypertension
ADRB2 obesity ADRB2 blood pressure, arterial ADRB2 Type 2 Diabetes
ADRB3 obesity ADRB3 Type 2 Diabetes ADRB3 hypertension AGT
hypertension AGT Type 2 diabetes AGT essential hypertension AGT
myocardial infarction AGTR1 hypertension AGTR2 hypertension AHR
breast cancer ALAD lead toxicity ALDH2 alcoholism ALDH2 alcohol
abuse ALDH2 colorectal cancer ALDRL2 Type 2 diabetes ALOX5 asthma
ALOX5AP asthma APBB1 Alzheimer's Disease APC colorectal cancer
APEX1 lung cancer APOA1 atherosclerosis, coronary APOA1
cholesterol, HDL APOA1 coronary artery disease APOA1 Type 2
diabetes APOA4 Type 2 diabetes APOA5 triglycerides APOA5
atherosclerosis, coronary APOB hypercholesterolemia APOB obesity
APOB cardiovascular APOB coronary artery disease APOB coronary
heart disease APOB Type 2 diabetes APOC1 Alzheimer's Disease APOC3
triglycerides APOC3 Type 2 Diabetes APOE Alzheimer's Disease APOE
Type 2 diabetes APOE multiple sclerosis APOE atherosclerosis,
coronary APOE Parkinson's disease APOE coronary heart disease APOE
myocardial infarction APOE stroke APOE Alzheimer's disease APOE
coronary artery disease APP Alzheimer's Disease AR prostate cancer
AR breast cancer ATM breast cancer ATP7B Wilson disease ATXN8OS
spinocerebellar ataxia BACE1 Alzheimer's Disease BCHE Alzheimer's
Disease BDKRB2 hypertension BDNF Alzheimer's Disease BDNF bipolar
disorder BDNF Parkinson's disease BDNF schizophrenia BDNF memory
BGLAP bone density BRAF thyroid cancer BRCA1 breast cancer BRCA1
breast cancer; ovarian cancer BRCA1 ovarian cancer BRCA2 breast
cancer BRCA2 breast cancer; ovarian cancer BRCA2 ovarian cancer
BRIP1 breast cancer C4A systemic lupus erythematosus CALCR bone
density CAMTA1 episodic memory CAPN10 diabetes, type 2 CAPN10 Type
2 diabetes CAPN3 muscular dystrophy CARD15 Crohn's disease CARD15
Crohn's disease; ulcerative colitis CARD15 Inflammatory Bowel
Disease CART obesity CASR bone density CCKAR schizophrenia CCL2
systemic lupus erythematosus CCL5 HIV CCL5 asthma CCND1 colorectal
cancer CCR2 HIV CCR2 HIV infection CCR2 hepatitis C CCR2 myocardial
infarct CCR3 Asthma CCR5 HIV CCR5 HIV infection CCR5 hepatitis C
CCR5 asthma CCR5 multiple sclerosis CD14 atopy CD14 asthma CD14
Crohn's disease CD14 Crohn's disease; ulcerative colitis CD14
periodontitis CD14 total IgE CDH1 prostate cancer CDH1 colorectal
cancer CDKN2A melanoma CDSN psoriasis CEBPA leukemia, myeloid CETP
atherosclerosis, coronary CETP coronary heart disease CETP
hypercholesterolemia CFH macular degeneration CFTR cystic fibrosis
CFTR pancreatitis CFTR Cystic Fibrosis CHAT Alzheimer's Disease
CHEK2 breast cancer CHRNA7 schizophrenia CMA1 atopic dermatitis
CNR1 schizophrenia COL1A1 bone density COL1A1 osteoporosis COL1A2
bone density COL2A1 osteoarthritis COMT schizophrenia COMT breast
cancer COMT Parkinson's disease COMT bipolar disorder COMT
obsessive compulsive disorder COMT alcoholism CR1 systemic lupus
erythematosus CRP C-reactive protein CST3 Alzheimer's Disease CTLA4
Type 1 diabetes CTLA4 Graves' disease CTLA4 multiple sclerosis
CTLA4 rheumatoid arthritis CTLA4 systemic lupus erythematosus CTLA4
lupus erythematosus CTLA4 celiac disease CTSD Alzheimer's Disease
CX3CR1 HIV CXCL12 HIV CXCL12 HIV infection CYBA atherosclerosis,
coronary CYBA hypertension CYP11B2 hypertension CYP11B2 left
ventricular hypertrophy CYP17A1 breast cancer CYP17A1 prostate
cancer CYP17A1 endometriosis CYP17A1 endometrial cancer CYP19A1
breast cancer CYP19A1 prostate cancer CYP19A1 endometriosis CYP1A1
lung cancer CYP1A1 breast cancer CYP1A1 colorectal cancer CYP1A1
prostate cancer CYP1A1 esophageal cancer CYP1A1 endometriosis
CYP1A1 cytogenetic studies CYP1A2 schizophrenia CYP1A2 colorectal
cancer CYP1B1 breast cancer CYP1B1 glaucoma CYP1B1 prostate cancer
CYP21A2 21-hydroxylase deficiency CYP21A2 congenital adrenal
hyperplasia CYP21A2 adrenal hyperplasia, congenital CYP2A6 smoking
behavior CYP2A6 nicotine CYP2A6 lung cancer CYP2C19 H. pylori
infection CYP2C19 phenytoin CYP2C19 gastric disease CYP2C8 malaria,
plasmodium falciparum CYP2C9 anticoagulant complications CYP2C9
warfarin sensitivity CYP2C9 warfarin therapy, response to CYP2C9
colorectal cancer CYP2C9 phenytoin CYP2C9 acenocoumarol response
CYP2C9 coagulation disorder CYP2C9 hypertension CYP2D6 colorectal
cancer CYP2D6 Parkinson's disease CYP2D6 CYP2D6 poor metabolizer
phenotype CYP2E1 lung cancer CYP2E1 colorectal cancer CYP3A4
prostate cancer CYP3A5 prostate cancer CYP3A5 esophageal cancer
CYP46A1 Alzheimer's Disease DBH schizophrenia DHCR7
Smith-Lemli-Opitz syndrome DISC1 schizophrenia DLST Alzheimer's
Disease DMD muscular dystrophy DRD2 alcoholism DRD2 schizophrenia
DRD2 smoking behavior
DRD2 Parkinson's disease DRD2 tardive dyskinesia DRD3 schizophrenia
DRD3 tardive dyskinesia DRD3 bipolar disorder DRD4 attention
deficit hyperactivity disorder DRD4 schizophrenia DRD4 novelty
seeking DRD4 ADHD DRD4 personality traits DRD4 heroin abuse DRD4
alcohol abuse DRD4 alcoholism DRD4 personality disorders DTNBP1
schizophrenia EDN1 hypertension EGFR lung cancer ELAC2 prostate
cancer ENPP1 Type 2 diabetes EPHB2 prostate cancer EPHX1 lung
cancer EPHX1 colorectal cancer EPHX1 cytogenetic studies EPHX1
chronic obstructive pulmonary disease/COPD ERBB2 breast cancer
ERCC1 lung cancer ERCC1 colorectal cancer ERCC2 lung cancer ERCC2
cytogenetic studies ERCC2 bladder cancer ERCC2 colorectal cancer
ESR1 bone density ESR1 bone mineral density ESR1 breast cancer ESR1
endometriosis ESR1 osteoporosis ESR2 bone density ESR2 breast
cancer estrogen receptor bone mineral density F2 coronary heart
disease F2 stroke F2 thromboembolism, venous F2 preeclampsia F2
thrombosis F5 thromboembolism, venous F5 preeclampsia F5 myocardial
infarct F5 stroke F5 stroke, ischemic F7 atherosclerosis, coronary
F7 myocardial infarct F8 hemophilia F9 hemophilia FABP2 Type 2
diabetes FAS Alzheimer's Disease FASLG multiple sclerosis FCGR2A
systemic lupus erythematosus FCGR2A lupus erythematosus FCGR2A
periodontitis FCGR2A rheumatoid arthritis FCGR2B lupus
erythematosus FCGR2B systemic lupus erythematosus FCGR3A systemic
lupus erythematosus FCGR3A lupus erythematosus FCGR3A periodontitis
FCGR3A arthritis FCGR3A rheumatoid arthritis FCGR3B periodontitis
FCGR3B periodontal disease FCGR3B lupus erythematosus FGB
fibrinogen FGB myocardial infarction FGB coronary heart disease
FLT3 leukemia, myeloid FLT3 leukemia FMR1 Fragile X syndrome FRAXA
Fragile X Syndrome FUT2 H. pylori infection FVL Factor V Leiden
G6PD G6PD deficiency G6PD hyperbilirubinemia GABRA5 bipolar
disorder GBA Gaucher disease GBA Parkinson's disease GCGR (FAAH,
body mass/obesity ML4R, UCP2) GCK Type 2 diabetes GCLM (F12, TLR4)
atherosclerosis, myocardial infarction GDNF schizophrenia GHRL
obesity GJB1 Charcot-Marie-Tooth disease GJB2 deafness GJB2 hearing
loss, sensorineural nonsyndromic GJB2 hearing loss, sensorineural
GJB2 hearing loss/deafness GJB6 hearing loss, sensorineural
nonsyndromic GJB6 hearing loss/deafness GNAS hypertension GNB3
hypertension GPX1 lung cancer GRIN1 schizophrenia GRIN2B
schizophrenia GSK3B bipolar disorder GSTM1 lung cancer GSTM1
colorectal cancer GSTM1 breast cancer GSTM1 prostate cancer GSTM1
cytogenetic studies GSTM1 bladder cancer GSTM1 esophageal cancer
GSTM1 head and neck cancer GSTM1 leukemia GSTM1 Parkinson's disease
GSTM1 stomach cancer GSTP1 Lung cancer GSTP1 colorectal cancer
GSTP1 breast cancer GSTP1 cytogenetic studies GSTP1 prostate cancer
GSTT1 lung cancer GSTT1 colorectal cancer GSTT1 breast cancer GSTT1
prostate cancer GSTT1 Bladder Cancer GSTT1 cytogenetic studies
GSTT1 asthma GSTT1 benzene toxicity GSTT1 esophageal cancer GSTT1
head and neck cancer GYS1 Type 2 diabetes HBB thalassemia HBB
thalassemia, beta HD Huntington's disease HFE Hemochromatosis HFE
iron levels HFE colorectal cancer HK2 Type 2 diabetes HLA
rheumatoid arthritis HLA Type 1 diabetes HLA Behcet's Disease HLA
celiac disease HLA psoriasis HLA Graves disease HLA multiple
sclerosis HLA schizophrenia HLA asthma HLA diabetes mellitus HLA
Lupus HLA-A leukemia HLA-A HIV HLA-A diabetes, type 1 HLA-A
graft-versus-host disease HLA-A multiple sclerosis HLA-B leukemia
HLA-B Behcet's Disease HLA-B celiac disease HLA-B Type 1 diabetes
HLA-B graft-versus-host disease HLA-B sarcoidosis HLA-C psoriasis
HLA-DPA1 measles HLA-DPB1 Type 1 diabetes HLA-DPB1 asthma HLA-DQA1
Type 1 diabetes HLA-DQA1 celiac disease HLA-DQA1 cervical cancer
HLA-DQA1 asthma HLA-DQA1 multiple sclerosis HLA-DQA1 Type 2
diabetes; Type 1 diabetes HLA-DQA1 lupus erythematosus HLA-DQA1
pregnancy loss, recurrent HLA-DQA1 psoriasis HLA-DQB1 Type 1
diabetes HLA-DQB1 celiac disease HLA-DQB1 multiple sclerosis
HLA-DQB1 cervical cancer HLA-DQB1 lupus erythematosus HLA-DQB1
pregnancy loss, recurrent HLA-DQB1 arthritis HLA-DQB1 asthma
HLA-DQB1 HIV HLA-DQB1 lymphoma HLA-DQB1 tuberculosis HLA-DQB1
rheumatoid arthritis HLA-DQB1 diabetes, type 2 HLA-DQB1
graft-versus-host disease HLA-DQB1 narcolepsy HLA-DQB1 arthritis,
rheumatoid HLA-DQB1 cholangitis, sclerosing HLA-DQB1 Type 2
diabetes; Type 1 diabetes HLA-DQB1 Graves' disease HLA-DQB1
hepatitis C HLA-DQB1 hepatitis C, chronic HLA-DQB1 malaria HLA-DQB1
malaria, plasmodium falciparum HLA-DQB1 melanoma HLA-DQB1 psoriasis
HLA-DQB1 Sjogren's syndrome HLA-DQB1 systemic lupus erythematosus
HLA-DRB1 Type 1 diabetes HLA-DRB1 multiple sclerosis HLA-DRB1
systemic lupus erythematosus HLA-DRB1 rheumatoid arthritis HLA-DRB1
cervical cancer HLA-DRB1 arthritis HLA-DRB1 celiac disease HLA-DRB1
lupus erythematosus HLA-DRB1 sarcoidosis HLA-DRB1 HIV HLA-DRB1
tuberculosis HLA-DRB1 Graves' disease HLA-DRB1 lymphoma HLA-DRB1
psoriasis HLA-DRB1 asthma HLA-DRB1 Crohn's disease HLA-DRB1
graft-versus-host disease HLA-DRB1 hepatitis C, chronic HLA-DRB1
narcolepsy HLA-DRB1 sclerosis, systemic HLA-DRB1 Sjogren's syndrome
HLA-DRB1 Type 1 diabetes HLA-DRB1 arthritis, rheumatoid HLA-DRB1
cholangitis, sclerosing HLA-DRB1 Type 2 diabetes; Type 1 diabetes
HLA-DRB1 H. pylori infection HLA-DRB1 hepatitis C HLA-DRB1 juvenile
arthritis HLA-DRB1 leukemia HLA-DRB1 malaria HLA-DRB1 melanoma
HLA-DRB1 pregnancy loss, recurrent HLA-DRB3 psoriasis HLA-G
pregnancy loss, recurrent HMOX1 atherosclerosis, coronary HNF4A
Type 2 diabetes HSD11B2 hypertension HSD17B1 breast cancer HTR1A
depressive disorder, major HTR1B alcohol dependence HTR1B
alcoholism HTR2A memory HTR2A schizophrenia HTR2A bipolar disorder
HTR2A depression HTR2A depressive disorder, major HTR2A suicide
HTR2A Alzheimer's Disease HTR2A anorexia nervosa HTR2A hypertension
HTR2A obsessive compulsive disorder HTR2C schizophrenia
HTR6 Alzheimer's Disease HTR6 schizophrenia HTRA1 wet age-related
macular degeneration IAPP Type 2 Diabetes IDE Alzheimer's Disease
IFNG tuberculosis IFNG Type 1 diabetes IFNG graft-versus-host
disease IFNG hepatitis B IFNG multiple sclerosis IFNG asthma IFNG
breast cancer IFNG kidney transplant IFNG kidney transplant
complications IFNG longevity IFNG pregnancy loss, recurrent IGFBP3
breast cancer IGFBP3 prostate cancer IL10 systemic lupus
erythematosus IL10 asthma IL10 graft-versus-host disease IL10 HIV
IL10 kidney transplant IL10 kidney transplant complications IL10
hepatitis B IL10 juvenile arthritis IL10 longevity IL10 multiple
sclerosis IL10 pregnancy loss, recurrent IL10 rheumatoid arthritis
IL10 tuberculosis IL12B Type 1 diabetes IL12B asthma IL13 asthma
IL13 atopy IL13 chronic obstructive pulmonary disease/COPD IL13
Graves' disease IL1A periodontitis IL1A Alzheimer's Disease IL1B
periodontitis IL1B Alzheimer's Disease IL1B stomach cancer IL1R1
Type 1 diabetes IL1RN stomach cancer IL2 asthma; eczema; allergic
disease IL4 Asthma IL4 atopy IL4 HIV IL4R asthma IL4R atopy IL4R
total serum IgE IL6 bone mineralization IL6 kidney transplant IL6
kidney transplant complications IL6 longevity IL6 multiple
sclerosis IL6 bone density IL6 bone mineral density IL6 colorectal
cancer IL6 juvenile arthritis IL6 rheumatoid arthritis IL9 asthma
INHA premature ovarian failure INS Type 1 diabetes INS Type 2
diabetes INS obesity INS prostate cancer INSIG2 obesity INSR Type 2
diabetes INSR hypertension INSR polycystic ovary syndrome IPF1 Type
2 diabetes IRS1 Type 2 diabetes IRS2 Type 2 diabetes ITGB3
myocardial infarction ITGB3 atherosclerosis, coronary ITGB3
coronary heart disease ITGB3 myocardial infarct KCNE1 EKG, abnormal
KCNE2 EKG, abnormal KCNH2 EKG, abnormal KCNH2 long QT syndrome
KCNJ11 diabetes, type 2 KCNJ11 Type 2 Diabetes KCNN3 schizophrenia
KCNQ1 EKG, abnormal KCNQ1 long QT syndrome KIBRA episodic memory
KLK1 hypertension KLK3 prostate cancer KRAS colorectal cancer LDLR
hypercholesterolemia LDLR hypertension LEP obesity LEPR obesity
LIG4 breast cancer LIPC atherosclerosis, coronary LPL coronary
artery disease LPL hyperlipidemia LPL triglycerides LRP1
Alzheimer's Disease LRP5 bone density LRRK2 Parkinson's disease
LRRK2 Parkinsons disease LTA Type 1 diabetes LTA asthma LTA
systemic lupus erythematosus LTA sepsis LTC4S asthma MAOA
alcoholism MAOA schizophrenia MAOA bipolar disorder MAOA smoking
behavior MAOA personality disorders MAOB Parkinson's disease MAOB
smoking behavior MAPT Parkinson's disease MAPT Alzheimer's Disease
MAPT dementia MAPT frontotemporal dementia MAPT progressive
supranuclear palsy MC1R melanoma MC3R obesity MC4R obesity MECP2
Rett syndrome MEFV Familial Mediterranean Fever MEFV amyloidosis
MICA Type 1 diabetes MICA Behcet's Disease MICA celiac disease MICA
rheumatoid arthritis MICA systemic lupus erythematosus MLH1
colorectal cancer MME Alzheimer's Disease MMP1 lung cancer MMP1
ovarian cancer MMP1 periodontitis MMP3 myocardial infarct MMP3
ovarian cancer MMP3 rheumatoid arthritis MPO lung cancer MPO
Alzheimer's Disease MPO breast cancer MPZ Charcot-Marie-Tooth
disease MS4A2 asthma MS4A2 atopy MSH2 colorectal cancer MSH6
colorectal cancer MSR1 prostate cancer MTHFR colorectal cancer
MTHFR Type 2 diabetes MTHFR neural tube defects MTHFR homocysteine
MTHFR thromboembolism, venous MTHFR atherosclerosis, coronary MTHFR
Alzheimer's Disease MTHFR esophageal cancer MTHFR preeclampsia
MTHFR pregnancy loss, recurrent MTHFR stroke MTHFR thrombosis, deep
vein MT-ND1 Type 2 diabetes MTR colorectal cancer MT-RNR1 hearing
loss, sensorineural nonsyndromic MTRR neural tube defects MTRR
homocysteine MT-TL1 Type 2 diabetes MUTYH colorectal cancer MYBPC3
cardiomyopathy MYH7 cardiomyopathy MYOC glaucoma, primary
open-angle MYOC glaucoma NAT1 colorectal cancer NAT1 breast cancer
NAT1 bladder cancer NAT2 colorectal cancer NAT2 bladder cancer NAT2
breast cancer NAT2 lung cancer NBN breast cancer NCOA3 breast
cancer NCSTN Alzheimer's Disease NEUROD1 Type 1 diabetes NF1
neurofibromatosis1 NOS1 asthma NOS2A multiple sclerosis NOS3
hypertension NOS3 coronary heart disease NOS3 atherosclerosis,
coronary NOS3 coronary artery disease NOS3 myocardial infarction
NOS3 acute coronary syndrome NOS3 blood pressure, arterial NOS3
preeclampsia NOS3 nitric oxide NOS3 Alzheimer's Disease NOS3 asthma
NOS3 Type 2 diabetes NOS3 cardiovascular disease NOS3 Behcet's
Disease NOS3 erectile dysfunction NOS3 kidney failure, chronic NOS3
lead toxicity NOS3 left ventricular hypertrophy NOS3 pregnancy
loss, recurrent NOS3 retinopathy, diabetic NOS3 stroke NOTCH4
schizophrenia NPY alcohol abuse NQO1 lung cancer NQO1 colorectal
cancer NQO1 benzene toxicity NQO1 bladder cancer NQO1 Parkinson's
disease NR3C2 hypertension NR4A2 Parkinson's disease NRG1
schizophrenia NTF3 schizophrenia OGG1 lung cancer OGG1 colorectal
cancer OLR1 Alzheimer's Disease OPA1 glaucoma OPRM1 alcohol abuse
OPRM1 substance dependence OPTN glaucoma, primary open-angle P450
drug metabolism PADI4 rheumatoid arthritis PAH phenylketonuria/PKU
PAI1 coronary heart disease PAI1 asthma PALB2 breast cancer PARK2
Parkinson's disease PARK7 Parkinson's disease PDCD1 lupus
erythematosus PINK1 Parkinson's disease PKA memory PKC memory
PLA2G4A schizophrenia PNOC schizophrenia POMC obesity PON1
atherosclerosis, coronary PON1 Parkinson's disease PON1 Type 2
diabetes PON1 atherosclerosis PON1 coronary artery disease PON1
coronary heart disease PON1 Alzheimer's Disease PON1 longevity PON2
atherosclerosis, coronary PON2 preterm delivery PPARG Type 2
diabetes
PPARG obesity PPARG Type 2 diabetes PPARG colorectal cancer PPARG
hypertension PPARGC1A Type 2 diabetes PRKCZ Type 2 diabetes PRL
systemic lupus erythematosus PRNP Alzheimer's Disease PRNP
Creutzfeldt-Jakob disease PRODH schizophrenia PRSS1 pancreatitis
PSEN1 Alzheimer's Disease PSEN2 Alzheimer's Disease PSMB8 Type 1
diabetes PSMB9 Type 1 diabetes PTCH skin cancer, non-melanoma PTGIS
hypertension PTGS2 colorectal cancer PTH bone density PTPN11 Noonan
syndrome PTPN22 rheumatoid arthritis PTPRC multiple sclerosis PVT1
end stage renal disease RAD51 breast cancer RAGE retinopathy,
diabetic RB1 retinoblastoma RELN schizophrenia REN hypertension RET
thyroid cancer RET Hirschsprung's disease RFC1 neural tube defects
RGS4 schizophrenia RHO retinitis pigmentosa RNASEL prostate cancer
RYR1 malignant hyperthermia SAA1 amyloidosis SCG2 hypertension SCG3
obesity SCGB1A1 asthma SCN5A Brugada syndrome SCN5A EKG, abnormal
SCN5A long QT syndrome SCNN1B hypertension SCNN1G hypertension
SERPINA1 COPD SERPINA3 Alzheimer's Disease SERPINA3 COPD SERPINA3
Parkinson's disease SERPINE1 myocardial infarct SERPINE1 Type 2
diabetes SERPINE1 atherosclerosis, coronary SERPINE1 obesity
SERPINE1 preeclampsia SERPINE1 stroke SERPINE1 hypertension
SERPINE1 pregnancy loss, recurrent SERPINE1 thromboembolism, venous
SLC11A1 tuberculosis SLC22A4 Crohn's disease; ulcerative colitis
SLC22A5 Crohn's disease; ulcerative colitis SLC2A1 Type 2 diabetes
SLC2A2 Type 2 diabetes SLC2A4 Type 2 diabetes SLC3A1 cystinuria
SLC6A3 attention deficit hyperactivity disorder SLC6A3 Parkinson's
disease SLC6A3 smoking behavior SLC6A3 alcoholism SLC6A3
schizophrenia SLC6A4 depression SLC6A4 depressive disorder, major
SLC6A4 schizophrenia SLC6A4 suicide SLC6A4 alcoholism SLC6A4
bipolar disorder SLC6A4 personality traits SLC6A4 attention deficit
hyperactivity disorder SLC6A4 Alzheimer's Disease SLC6A4
personality disorders SLC6A4 panic disorder SLC6A4 alcohol abuse
SLC6A4 affective disorder SLC6A4 anxiety disorder SLC6A4 smoking
behavior SLC6A4 depressive disorder, major; bipolar disorder SLC6A4
heroin abuse SLC6A4 irritable bowel syndrome SLC6A4 migraine SLC6A4
obsessive compulsive disorder SLC6A4 suicidal behavior SLC7A9
cystinuria SNAP25 attention deficit hyperactivity disorder SNCA
Parkinson's disease SOD1 ALS/amyotrophic lateral sclerosis SOD2
breast cancer SOD2 lung cancer SOD2 prostate cancer SPINK1
pancreatitis SPP1 multiple sclerosis SRD5A2 prostate cancer STAT6
asthma STAT6 total IgE SULT1A1 breast cancer SULT1A1 colorectal
cancer TAP1 Type 1 diabetes TAP1 lupus erythematosus TAP2 Type 1
diabetes TAP2 diabetes, type 1 TBX21 asthma TBXA2R asthma TCF1 Type
2 diabetes TF Alzheimer's Disease TGFB1 breast cancer TGFB1 kidney
transplant TGFB1 kidney transplant complications TH schizophrenia
THBD myocardial infarction TLR4 asthma TLR4 Crohn's disease;
ulcerative colitis TLR4 sepsis TNF asthma TNFA cerebrovascular
disease TNF Type 1 diabetes TNF rheumatoid arthritis TNF systemic
lupus erythematosus TNF kidney transplant TNF psoriasis TNF sepsis
TNF Type 2 diabetes TNF Alzheimer's Disease TNF Crohn's disease TNF
hepatitis B TNF kidney transplant complications TNF multiple
sclerosis TNF schizophrenia TNF celiac disease TNF obesity TNF
pregnancy loss, recurrent TNFRSF11B bone density TNFRSF1A
rheumatoid arthritis TNFRSF1B rheumatoid arthritis TNFRSF1B
systemic lupus erythematosus TNFRSF1B arthritis TNNT2
cardiomyopathy TP53 lung cancer TP53 breast cancer TP53 colorectal
cancer TP53 prostate cancer TP53 cervical cancer TP53 ovarian
cancer TP53 smoking TP53 esophageal cancer TP73 lung cancer TPH1
suicide TPH1 depressive disorder, major TPH1 suicidal behavior TPH1
schizophrenia TPMT thiopurine methyltransferase activity TPMT
leukemia TPMT inflammatory bowel disease TPMT thiopurine
S-methyltransferase phenotype TSC1 tuberous sclerosis TSC2 tuberous
sclerosis TSHR Graves' disease TYMS colorectal cancer TYMS stomach
cancer TYMS esophageal cancer UCHL1 Parkinson's disease UCP1
obesity UCP2 obesity UCP3 obesity UGT1A1 hyperbilirubinemia UGT1A1
Gilbert syndrome UGT1A6 colorectal cancer UGT1A7 colorectal cancer
UTS2 diabetes, type 2 VDR bone density VDR prostate cancer VDR bone
mineral density VDR Type 1 diabetes VDR osteoporosis VDR bone mass
VDR breast cancer VDR lead toxicity VDR tuberculosis VDR Type 2
diabetes VEGF breast cancer vit D rec idiopathic short stature
VKORC1 warfarin therapy, response to WNK4 hypertension XPA lung
cancer XPC lung cancer XPC cytogenetic studies XRCC1 lung cancer
XRCC1 cytogenetic studies XRCC1 breast cancer XRCC1 bladder cancer
XRCC2 breast cancer XRCC3 breast cancer XRCC3 cytogenetic studies
XRCC3 lung cancer XRCC3 bladder cancer ZDHHC8 schizophrenia
[0128] The following examples illustrate and explain the invention.
The scope of the invention is not limited by these examples.
EXAMPLE I
Generation and Analysis of SNP Profile
[0129] The individual is provided a sample tube in the kit, such as
that available from DNA Genotek, into which the individual deposits
a sample of saliva (approximately 4 mls) from which genomic DNA
will be extracted. The saliva sample is sent to a CLIA certified
laboratory for processing and analysis. The sample is typically
sent to the facility by overnight mail in a shipping container that
is conveniently provided to the individual in the collection
kit.
[0130] In a preferred embodiment, genomic DNA is isolated from
saliva. For example, using DNA self collection kit technology
available from DNA Genotek, an individual collects a specimen of
about 4 ml saliva for clinical processing. After delivery of the
sample to an appropriate laboratory for processing, DNA is isolated
by heat denaturing and protease digesting the sample, typically
using reagents supplied by the collection kit supplier at
50.degree. C. for at least one hour. The sample is next
centrifuged, and the supernatant is ethanol precipitated. The DNA
pellet is suspended in a buffer appropriate for subsequent
analysis.
[0131] The individual's genomic DNA is isolated from the saliva
sample, according to well known procedures and/or those provided by
the manufacturer of a collection kit. Generally, the sample is
first heat denatured and protease digested. Next, the sample is
centrifuged, and the supernatant is retained. The supernatant is
then ethanol precipitated to yield a pellet containing
approximately 5-16 ug of genomic DNA. The DNA pellet is suspended
in 10 mM Tris pH 7.6, 1 mM EDTA (TE). A SNP profile is generated by
hybridizing the genomic DNA to a commercially available high
density SNP array, such as those available from Affymetrix or
Illumina, using instrumentation and instructions provided by the
array manufacturer. The individual's SNP profile is deposited into
a secure database or vault.
[0132] The patient's data structure is queried for risk-imparting
SNPs by comparison to a clinically-derived database of established,
medically relevant SNPs whose presence in a genome correlates to a
given disease or condition. The database contains information of
the statistical correlation of particular SNPs and SNP haplotypes
to particular diseases or conditions. For example, as shown in
Example III, polymorphisms in the apolipoprotein E gene give rise
to differing isoforms of the protein, which in turn correlate with
a statistical likelihood of developing Alzheimer's Disease. As
another example, individuals possessing a variant of the blood
clotting protein Factor V known as Factor V Leiden have an
increased tendency to clot. A number of genes in which SNPs have
been associated to a disease or condition phenotype are shown in
Table 1. The information in the database is approved by a
research/clinical advisory board for its scientific accuracy and
importance, and may be reviewed with governmental agency oversight.
The database is continually updated as more SNP-disease
correlations emerge from the scientific community.
[0133] The results of the analysis of an individual's SNP profile
is securely provided to patient by an on-line portal or mailings.
The patient is provided interpretation and supportive information,
such as the information shown for Factor V Leiden in Example IV.
Secure access to the individual's SNP profile information, such as
through an on-line portal, will facilitate discussions with the
patient's physician and empower individual choices for personalized
medicine.
EXAMPLE II
Update of Genotype Correlations
[0134] In response to a request for an initial determination of an
individual's genotype correlations, a genomic profile is generated,
genotype correlations are made, and the results are provided to the
individual as described in Example I. Following an initial
determination of an individual's genotype correlations, subsequent,
updated correlations are or can be determined as additional
genotype correlations become known. The subscriber has a premium
level subscription and their genotype profile and is maintained in
a secure database. The updated correlations are performed on the
stored genotype profile.
[0135] For example, an initial genotype correlation, such as
described above in Example I, could have determined that a
particular individual does not have ApoE4 and thus is not
predisposed to early-onset Alzheimer's Disease, and that this
individual does not have Factor V Leiden. Subsequent to this
initial determination, a new correlation could become known and
validated, such that polymorphisms in a given gene, hypothetically
gene XYZ, are correlated to a given condition, hypothetically
condition 321. This new genotype correlation is added to the master
database of human genotype correlations. An update is then provided
to the particular individual by first retrieving the relevant gene
XYZ data from the particular individual's genomic profile stored in
a secure database. The particular individual's relevant gene XYZ
data is compared to the updated master database information for
gene XYZ. The particular individual's susceptibility or genetic
predisposition to condition 321 is determined from this comparison.
The results of this determination are added to the particular
individual's genotype correlations. The updated results of whether
or not the particular individual is susceptible or genetically
predisposed to condition 321 is provided to the particular
individual, along with interpretative and supportive
information.
EXAMPLE III
Correlation of ApoE4 Locus and Alzheimer's Disease
[0136] The risk of Alzheimer's disease (AD) has been shown to
correlate with polymorphisms in the apolipoprotein E (APOE) gene,
which gives rise to three isoforms of APOE referred to as ApoE2,
ApoE3, and ApoE4. The isoforms vary from one another by one or two
amino acids at residues 112 and 158 in the APOE protein. ApoE2
contains 112/158 cys/cys; ApoE3 contains 112/158 cys/arg; and ApoE4
contains 112/158 arg/arg. As shown in Table 2, the risk of
Alzeimer's disease onset at an earlier age increases with the
number of APOE .epsilon.4 gene copies. Likewise, as shown in Table
3, the relative risk of AD increases with number of APOE .epsilon.4
gene copies.
TABLE-US-00002 TABLE 2 Prevalence of AD Risk Alleles (Corder et
al., Science: 261: 921-3, 1993) APOF .epsilon.4 Alzheimer's Copies
Prevalence Risk Onset Age 0 73% 20% 84 1 24% 47% 75 2 3% 91% 68
TABLE-US-00003 TABLE 3 Relative Risk of AD with ApoE4 (Farrer et
al., JAMA: 278: 1349-56, 1997) APOE Genotype Odds Ratio
.epsilon.2.epsilon.2 0.6 .epsilon.2.epsilon.3 0.6
.epsilon.3.epsilon.3 1.0 .epsilon.2.epsilon.4 2.6
.epsilon.3.epsilon.4 3.2 .epsilon.4.epsilon.4 14.9
EXAMPLE IV
Information for Factor V Leiden Positive Patient
[0137] The following information is exemplary of information that
could be supplied to an individual having a genomic SNP profile
that shows the presence of the gene for Factor V Leiden. The
individual may have a basic subscription in which the information
may be supplied in an initial report.
What is Factor V Leiden?
[0138] Factor V Leiden is not a disease, it is the presence of a
particular gene that is passed on from one's parents. Factor V
Leiden is a variant of the protein Factor V (5) which is needed for
blood clotting. People who have a Factor V deficiency are more
likely to bleed badly while people with Factor V Leiden have blood
that has an increased tendency to clot.
[0139] People carrying the Factor V Leiden gene have a five times
greater risk of developing a blood clot (thrombosis) than the rest
of the population. However, many people with the gene will never
suffer from blood clots. In Britain and the United States, 5 per
cent of the population carry one or more genes for Factor V Leiden,
which is far more than the number of people who will actually
suffer from thrombosis.
How Do You Get Factor V Leiden?
[0140] The genes for the Factor V are passed on from one's parents.
As with all inherited characteristics, one gene is inherited from
the mother and one from the father. So, it is possible to inherit:
-two normal genes or one Factor V Leiden gene and one normal gene
-or two Factor V Leiden genes. Having one Factor V Leiden gene will
result in a slightly higher risk of developing a thrombosis, but
having two genes makes the risk much greater.
What are the Symptoms of Factor V Leiden?
[0141] There are no signs, unless you have a blood clot
(thrombosis).
What are the Danger Signals?
[0142] The most common problem is a blood clot in the leg. This
problem is indicated by the leg becoming swollen, painful and red.
In rarer cases a blood clot in the lungs (pulmonary thrombosis) may
develop, making it hard to breathe. Depending on the size of the
blood clot this can range from being barely noticeable to the
patient experiencing severe respiratory difficulty. In even rarer
cases the clot might occur in an arm or another part of the body.
Since these clots formed in the veins that take blood to the heart
and not in the arteries (which take blood from the heart), Factor V
Leiden does not increase the risk of coronary thrombosis.
What can be Done to Avoid Blood Clots?
[0143] Factor V Leiden only slightly increases the risk of getting
a blood clot and many people with this condition will never
experience thrombosis. There are many things one can do to avoid
getting blood clots. Avoid standing or sitting in the same position
for long periods of time. When traveling long distances, it is
important to exercise regularly--the blood must not `stand still`.
Being overweight or smoking will greatly increase the risk of blood
clots. Women carrying the Factor V Leiden gene should not take the
contraceptive pill as this will significantly increase the chance
of getting thrombosis. Women carrying the Factor V Leiden gene
should also consult their doctor before becoming pregnant as this
can also increase the risk of thrombosis.
How Does a Doctor Find Out if You Have Factor V Leiden?
[0144] The gene for Factor V Leiden can be found in a blood
sample.
[0145] A blood clot in the leg or the arm can usually be detected
by an ultrasound examination.
[0146] Clots can also be detected by X-ray after injecting a
substance into the blood to make the clot stand out. A blood clot
in the lung is harder to find, but normally a doctor will use a
radioactive substance to test the distribution of blood flow in the
lung, and the distribution of air to the lungs. The two patterns
should match--a mismatch indicates the presence of a clot.
How is Factor V Leiden Treated?
[0147] People with Factor V Leiden do not need treatment unless
their blood starts to clot, in which case a doctor will prescribe
blood-thinning (anticoagulant) medicines such as warfarin (e.g.
Marevan) or heparin to prevent further clots. Treatment will
usually last for three to six months, but if there are several
clots it could take longer. In severe cases the course of drug
treatment may be continued indefinitely; in very rare cases the
blood clots may need to be surgically removed.
How is Factor V Leiden Treated During Pregnancy?
[0148] Women carrying two genes for Factor V Leiden will need to
receive treatment with a heparin coagulant medicine during
pregnancy. The same applies to women carrying just one gene for
Factor V Leiden who have previously had a blood clot themselves or
who have a family history of blood clots.
[0149] All women carrying a gene for Factor V Leiden may need to
wear special stockings to prevent clots during the last half of
pregnancy. After the birth of the child they may be prescribed the
anticoagulant drug heparin.
Prognosis
[0150] The risk of developing a clot increases with age, but in a
survey of people over the age of 100 who carry the gene, it was
found that only a few had ever suffered from thrombosis. The
National Society for Genetic Counselors (NSGC) can provide a list
of genetic counselors in your area, as well as information about
creating a family history. Search their on-line database at
www.nsgc.org/consumer.
[0151] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *
References