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Race, Genes and Common Diseases

Race, Genes and Common Diseases. Richard Cooper, MD Department of Preventive Medicine, Loyola Stritch School of Medicine. A Historical Note . . How many chromosomes do blacks and whites have?. From 1914 – when the accepted number was 48 for whites -

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Race, Genes and Common Diseases

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  1. Race, Genes and Common Diseases Richard Cooper, MD Department of Preventive Medicine, Loyola Stritch School of Medicine

  2. A Historical Note . . How many chromosomes do blacks and whites have? From 1914 – when the accepted number was 48 for whites - “Because Winiwarter had worked with Caucasian specimens and some of the 24 counts were from individuals of African descent, the suggestion was made that blacks and whites might differ by a factor of two in their chromosome number . . . No less a geneticists than Thomas H. Morgan considered such variation a possibility and mentioned it in his textbook”. Cited in Nature Reviews Genetics August 2006, page 655

  3. From Gene Discovery to Medical and Public Health Action • Gene Discovery • Gene location, function, variants • Gene Characterization • Prevalence, associations, interactions • Assessing Genetic Tests • Analytic validity • Clinical validity and utility • Ethical, social, legal implications • Population impact

  4. Defining the Basic Architecture of Genetic Variation Tractable forms of variation for study by genetic epidemiology: Common SNPs, and to a lesser extent rare SNPS – In coding regions, and potentially regulatory elements (ie, promoters, enhancers) But are these the sole, or even most important, types of variation?

  5. Genes and Variation in Disease Risk • Single Gene Disorders: Rare/uncommon mutations, but with large effect. Result of founder effects; restricted to sub-populations: Tay Sachs, Cystic Fibrosis Or – rarely – selection; defined by geography: Thalessemia, sickle cell • Common Complex Disorders: Many mutations are present, but each with small effects; Susceptibility is common in all populations - (Eg, Hypertension – lifetime incidence risk > 80%)

  6. Candidates for Genetic Screening Tests in Adults GeneCondition HFE Hereditary hemochromatosis APOE 4 Alzheimer’s CYP2D6 Cytochrome P452 activity BRCA 1 Breast cancer BRCA 2 Breast cancer Factor V Leiden Venous thrombosis APC Familial adenomatous polyposis ? TCF7L2 Diabetes

  7. Potential Impact of Molecular Genetics on Medicine and Public Health Questions: • Can molecular genetics help us understand the mechanisms of common disease – including the basis for variation in individual susceptibility? • How are those developments likely to interact with our understanding of race and racial variation in disease?

  8. Health Status Measures in US Racial/Ethnic Groups, 2001 White Black Hispanic Asian Cause of DeathAge – Adjusted Death Rates 842.9 245.6 177.5 56.0 197.4 47.0 21.7 22.1 2.1 1101.2 316.9 211.6 78.8 243.1 30.9 24.1 49.2 22.8 658.7 192.2 149.9 44.9 132.3 20.7 20.5 36.7 6.2 492.1 137.6 103.0 51.2 119.5 17.7 19.0 16.9 0.7 All Causes Heart Disease Coronary Heart Disease Stroke Cancer COPD Pneumonia / Influenza Diabetes mellitus HIV infection Infant Mortality (/1000) Life Expectancy 5.7 77.7 13.5 72.2 5.4 >80? 4.7 >80? Data Source: National Center for Health Statistics. Health, United States, 2003 With Chartbook on Trends in the Health of Americans. Hyattsville, Maryland: 2003.

  9. Origins and Destinations of European Trans-Atlantic Slave Trade

  10. Prevalence of Diabetes, by Race, Ages 20+ 2000, US Prevalence (%) White 7.8 Hispanic 10.2 Black 13.0 Amerindian 15.1 (NIDDK, NIH)

  11. Bias in the medical literature on race has a long history. . . “There is strong epidemiologic evidence that certain racial groups are more prone to diabetes than others.... There is every possibility that American blacks, descended from African blacks, could have a gene pool that makes them more susceptible to diabetes and also more severely affected with it once they have it . . . . .” Diabetes Care 1990;(Suppl 4), 1144

  12. Race and Diabetes . . . “The most straightforward interpretation of the observation that African-American race has a strong, independent associations with diabetes mellitus is that African-Americans are more susceptible to diabetes compared with white counterparts.” Annals of Epidemiology 1996;6:67

  13. The CDC Office of Genetics and Disease Prevention Interprets Epidemiologic Data . . . “The elevated risk of CV disease in minority women, long thought to be primarily the result of SES, may well be more closely related to race than once believed, researchers at Stanford report this week in JAMA. Differences in blood pressure, body mass index and diabetes persisted.. even after adjusting for years of education, indications that race itself plays a role.. (leading) the researchers to say that genetic factors may come into play.”

  14. SES, Race and Health Outcomes Age-Adjusted Rate SES vs. Disease Rate Blacks Whites Black % White Education

  15. Race and Health Status, Expected Results After Adjustment for SES Age-Adjusted Rate SES vs. Rate Whites Blacks Black % White Power/Wealth/Privilege

  16. Race and Health Status, Actual Results After Adjustment for EDUCATION Age-Adjusted Rate SES vs. Rate Blacks Whites Black % White Power/Wealth/Privilege

  17. Rates of Low Birthweight in Blacks & Whites, by Education: Georgia , 1980 - 87 180 160 140 120 100 80 60 40 20 0 Blacks Whites Low Birth WT (%) 12 <12 >12 Years of Education

  18. Rates of Low Birthweight in Blacks, by Education & Marital Status 200 180 160 140 120 100 80 60 40 20 0 Unmarried Married Low Birth WT / 1,000 <12 12 >12 Years of Education

  19. The primary logical fallacy created by racial bias in the pre-genomic era - Differences in prevalence rates among populations cannot be interpreted as evidence of a genetic effect.

  20. Criteria to Assess Whether A Racial Health Differential is likely to be Environmental or Genetic Differentials are likely to be driven by environment if: 1. Social class gradients exist within all races 2. Important environmental risk factors are known 3. Large temporal trends are present 4. Rates are different in the same race living in different countries or social settings.

  21. Prevalence of Diabetes, By Education, Ages 18+, 2001, US Prevalence (%) < High School 12.5 High School 7.0 Some post-HS 5.9 College 4.2 (BRFSS, CDC)

  22. Prevalence of Type 2 Diabetes and Mean Population BMI Men/Women Combined 70 caucasian 60 middle eastern india/maur african/carib 50 asian pacific isl 40 % Diabetes south/cent am 30 20 10 0 20 25 30 35 40 Mean BMI

  23. H y p e r t e n s i o n d e f i n e d a s S y s t o l i c B l o o d P r e s s u r e > 1 4 0 o r D i a s t o l i c B l o o d P r e s s u r e > 9 0 o r t a k i n g A n t i - h y p e r t e n s i o n M e d i c a t i o n Prevalence of Hypertension Among Six Populations of West African Origin: ICSHIB, 1995 0 . 4 0 0 . 3 5 0 . 3 0 0 . 2 5 Percent Hypertensive 0 . 2 0 0 . 1 5 0 . 1 0 0 . 0 5 0 . 0 0 M a y w o o d B a r b a d o s J a m a i c a S t . L u c i a C a m e r o o n N i g e r i a Cooper et al, AJPH, 1997

  24. Age- and Gender- Adjusted Hypertension Prevalence, by Country and Race* 60 50 40 Hypertension Prevalence (%) 30 20 10 0 Nigeria Jamaica US White Sweden Italy England US Black Spain Finland Germany *Ages 35-64 Cooper et al, BMC, 2005

  25. BRFSS, CDC, US

  26. “The Race Factor” LA Times, Sept 8, 2003 “Researchers long believed that social, environmental and economic stresses of lower-income status explained (health differentials) . . . But they could not ignore a growing mountain of research. Some racial differences are encoded in the genes, and those differences can make people of one skin color inherently more or less susceptible to certain diseases than people whose complexion is different. In short, in matters of health, race matters.”

  27. Searching for Differences in Susceptibility across Racial Groups • Association - or case-control - studies of DNA polymorphisms (ie, mutations) in specific genes that vary in frequency across groups • Cluster analysis • 3. Admixture analysis • 4. Looking for differential evidence of selection across racial groups

  28. Alpha2 and Beta1 Adregergic Receptor Variants and Heart Failure Alpha2 Blacks- Controls Cases Whites - Controls Cases Beta1 Blacks - Controls Cases Whites- Controls Cases Allele Frequency .41 .62 .04 .10 .56 .53 .76 .74 Odds Ratio 5.7 3.9 0.9 0.8 Small et al, NEJM, 2002

  29. Gene-Gene Interactions of Alpha2 and Beta1 Adrengergic Receptor Variants and Heart Failure N with genotype 15 2 2 3 N for Total Sample 78 84 81 105 Odds Ratio 10.0 2.1 Blacks - Cases Controls Whites - Cases Controls Small et al, NEJM, 2002

  30. Gene Variants Tied to Heart Failure in Blacks (Oct 10, Reuters Health) Researchers have linked two common gene variations to an increased risk of congestive heart failure among black Americans. “This level of synergy has never been seen before in a cardiovascular gene,”. . . . It is possible, then, that these gene variations contribute to black Americans’ particularly high risk of CHF, he said.

  31. November 2005 Odds Allelle Frequency RatioCasesControlsPAR Whites 1.16 .17 .15 2% Blacks 3.50 .11 .03 7% PAR = population attributable risk

  32. May 2006 Odds Allelle Frequency RatioCasesControlsPAR Whites 1.62 .19 .13 8% Blacks 1.60 .41 .30 16% “ . . this genetic variant . . could produce 10% greater incidence in African Americans . . PAR = population attributable risk

  33. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Grant et al. Odds Ratio Homozygotes 1.5 . Heterozygotes 2.4 Allelle frequency = 26% Introduction: “There is evidence of a genetic component to the risk of type 2 diabetes, including prevalence differences between racial groups . . . .”

  34. Relative Allelle RiskFrequency Whites 1.7 33% Blacks 1.2 31%

  35. American Journal of Human Genetics, 2006

  36. Genetic Effects of PCSK9 on Lipoprotein Levels in African-Americans Cohen et al. N Engl J Med2006

  37. CHD Reduced 88% in African-Americans with PCSK9 – Y142X or C679X 12 8 Coronary Heart Disease (%) 4 * - PCSK9 mutations + Y142X or C679X * P = 0.008 Hazard ratio = 0.11 (CI: 0.02-0.8, P=0.03) Cohen et al. N Engl J Med2006

  38. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Grant et al. Relative Risk, Heterozygotes = 1.5 Homozygotes = 2.4 Frequency of the variant = 26%

  39. African Origin of Anatomically Modern Humans Adapted from Hedges, 2000, Nature 408: 652-3

  40. Most genetic variants are shared among populations Africa 18 11 3 33 Asia Europe 1 2 6 Jorde et al 2005

  41. Estimated World Population Structure Based on 52 Populations Rosenberg et al, Science, 2002

  42. Categorization of humans in biomedical research: genes, race and disease. Risch N, et al. Genome Biology 2002;3/7/comment 2007.1-2007.12 • “- Genetic studies have recapitulated the classical definition of races based on continental ancestry… • - Genetic differentiation is greatest when defined on a continental basis… • If biological is defined by susceptibility to and natural history of a chronic disease, than numerous studies over past decades have documented biological differences among races …”

  43. Geographic Clustering Based on Alu Polymorphisms. Jorde and Wooding, Nat Genetics 2004

  44. A Neighbor-joining Tree Based on Variants in Angiotensinogen Jorde and Wooding, Nat Genetics 2004

  45. Admixture Mapping Two types of admixture mapping: “Global” - assumes that one of the ancestral populations has higher average risk, and tests whether genetic factors are a likely explanation. Actually association; prone to Type 1 error. “Locus specific” – assumes that the influential loci vary among populations, and attempts to localize the variant in the admixed population. Can be a test of linkage, under appropriate circumstances.

  46. Admixture mapping for hypertension loci with genome-scan markers. Zhu et al, Nature Genetics 2005

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