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Genetic Epidemiology Genetic Epidemiology as a Probe for Disease Biologyas a Probe for Disease Biology
Genetic Epidemiology Genetic Epidemiology as a Probe for Disease Biologyas a Probe for Disease Biology
Mehmet Tevfik DORAK, MD PhDMehmet Tevfik DORAK, MD PhD
Dept of Environmental & Occupational HealthDept of Environmental & Occupational HealthRobert Stempel College of Public Health and Social WorkRobert Stempel College of Public Health and Social Work
Mehmet Tevfik DORAK, MD PhDMehmet Tevfik DORAK, MD PhD
Dept of Environmental & Occupational HealthDept of Environmental & Occupational HealthRobert Stempel College of Public Health and Social WorkRobert Stempel College of Public Health and Social Work
College of Medicine, FIUApril 15, 2011
OUTLINEOUTLINE
General introduction to epidemiology, genetic epidemiology and genetic association studies
Success stories leading to ?
Real power of genetic association studies
Conclusions
OUTLINEOUTLINE
General introduction to epidemiology, genetic epidemiology and genetic association studies
Success stories leading to ?
Real power of genetic association studies
Conclusions
PLoS Med. 2005 Aug;2(8):e124.
WSJ. 2004Sep14.
Case-control genetic association studies are more common than cohort studies or
linkage studies
Why?Why?
- They are cheaper- They are easier- They are quick
- They are easier to analyze
Of course, genetic association studies are performed to find the causal genetic
polymorphisms and to learn more about disease biology.
- They are cheaper- They are easier- They are quick
- They are easier to analyze
However, these advantages have been exploited by many in need of a quick
publication!
Hierarchy of Epidemiologic Study DesignHierarchy of Epidemiologic Study Design
Tower & Spector, 2007 (www)
When used for scientific enquiries, however, genetic association studies yield
very informative results
Following is a brief history of genetic epidemiology and examples of good use of
genetic association studies
Handbook of Statistical Genetics(John Wiley & Sons)Fig.28-1 (www)
GENETIC EPIDEMIOLOGIC RESEARCH METHODS
ROCHE Genetic Education (www)
Odds Ratio: 3.695% CI = 1.3 to 10.4
Martin, 2000 (www)
Mapping Disease Susceptibility Genes by Association Studies
Plot of minus log of P value for case-control test for allelic association with AD, for SNPs immediately surrounding APOE (<100 kb)
(www)
Mapping Disease Susceptibility Genes by Association Studies
GWAS Success Stories
The most robust association in GWAS to date
rs380390
GWAS Success Stories
The most robust association in GWAS to date
rs380390 >>> Y402HOR = 7.4 (r)
96 cases & 50 controls
• Chromosomal region 1q31 where CFH maps had been identified as a
candidate region in six linkage studies
• Activated C5b-9 complex has been detected in patients with AMD
• Complement factor H levels increase with age and in smokers; two
risk factors for AMD
• Complement factor H is detectable in the eye
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
GWAS Success Stories
(www)
GWAS Success Stories ??
(www)
(www)
It is therefore unlikely that as we perform them now even GWAS do not have sufficient power to decode
the substantial portion of genetic component in disease susceptibility.
Genetic Association Studies are Particularly Powerful:
- To test whether reverse causation is involved (iron deficiency in GI tract cancers; low cholesterol in cancer)
- To unravel effect modification (by gender or an environmental factor)
Genetic association results are cumulative results determined by the whole body and environment unlike results of in vitro experiments on a single cell under extremely controlled
environments
In a case-control study:
• Cause and effect relationship is not clear • The observed association may be caused by a confounder • It may be due to chance • Reverse causation cannot be ruled out
Mendelian randomization may be relied on when the confounder is suspected but not known
Randomization is naturally achieved in genetic association studies
Cause-and-Effect Relationship is Easier to Assess Cause-and-Effect Relationship is Easier to Assess in Genetic Association Studies in Genetic Association Studies
Grimes & Schulz, 2002 (www) (PDF)
(www)
Effect Modification by an Environmental Factor
wtwt
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variantvariant
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protectionprotection
riskrisk
High cancer riskHigh cancer risk
low iron levelslow iron levels
High cancer riskHigh cancer risk
high iron levelshigh iron levels
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Iron Regulatory Gene Variants and Modification of Cancer Risk
Mendelian Randomization
Effect Modification by Gender Effect Modification by Gender
Despite that males and females are Despite that males and females are almost different species, the gender almost different species, the gender
effect is almost always disregarded in the effect is almost always disregarded in the analysis of biomedical research resultsanalysis of biomedical research results
• IBD3 maps to chromosome 6p in linkage studies and known as the HLA-linked IBD susceptibility locus
Inflammatory Bowel Disease Inflammatory Bowel Disease
HLA-DRB4 Association in Childhood ALL
Homozygosity for HLA-DRB4 family is associated with susceptibility to childhood ALL
in boys only (P < 0.0001, OR = 6.1, 95% CI = 2.9 to 12.6 )
Controls are an unselected group of local newborns (201 boys & 214 girls)
* Case-only analysis P = 0.002 (OR = 5.6; 95% CI = 1.8 to 17.6)
%%
Boys, n=64
*
Girls, n=53
*
Effect Modification by Gender Effect Modification by Gender
HMOX1 5’ flanking regionHMOX1 5’ flanking region
rs5755709 G>A
-10kb -416
rs2071746 A>TSTR
P (sex) = 0.015P (sex; case-only) = 0.01
Effect Modification by Gender Effect Modification by Gender
NRAMP2 rs422982 shows sex-specific associations in childhood leukemiaNRAMP2 rs422982 shows sex-specific associations in childhood leukemia
Effect Modification by Gender Effect Modification by Gender
CONCLUSIONSCONCLUSIONS
Observational epidemiologic studies are useful to explore disease biology and generate hypotheses
when used appropriately
Identification of the whole of genetic component of disease susceptibility requires more than DNA
sequence analysis
Dorak Lab is open for business!
CONCLUSIONSCONCLUSIONS
Observational epidemiologic studies are useful to explore disease biology and generate hypotheses
when used appropriately
Identification of the whole of genetic component of disease susceptibility requires more than DNA
sequence analysis
Dorak Lab is open for business!
ACKNOWLEDGMENTSACKNOWLEDGMENTS
Anyone who has ever taught me anything
My current teamMalar, Amy and Sandeep
Florida International UniversityRSCPHSW
EOH
ACKNOWLEDGMENTSACKNOWLEDGMENTS
Anyone who has ever taught me anything
My current teamMalar, Amy and Sandeep
Florida International UniversityRSCPHSW
EOH
