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HOWEVER. Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans Genovese et al Science, July 2010. Fig. 1 Association analysis in FSGS cohorts with logistic regression for alleles G1 and G2. G Genovese et al. Science 2010;329:841-845. Published by AAAS.

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HOWEVER

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  1. HOWEVER

  2. Association of Trypanolytic ApoL1 Variants with Kidney Disease in African Americans Genovese et al Science, July 2010

  3. Fig. 1 Association analysis in FSGS cohorts with logistic regression for alleles G1 and G2. G Genovese et al. Science 2010;329:841-845 Published by AAAS

  4. Here, we show that, in African Americans, focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22 {FSGS odds ratio = 10.5 [95% confidence interval (CI) 6.0 to 18.4]; H-ESKD odds ratio = 7.3 (95% CI 5.6 to 9.5)}. The two APOL1 variants are common in African chromosomes but absent from European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. ApoL1 (apolipoprotein L-1) is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease–associated ApoL1 variants lysed Trypanosoma brucei rhodesiense. We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans.

  5. Individual Ancestry and High Density SNP chips • A chromosome from an individual of recent admixed ancestry constitutes a patchwork of chromosomal segments of distinct ancestry (ancestry blocks). • Dense SNP chips (e.g. 500K random SNPs) can be used to accurately recreate ancestry blocks. Therefore, GWA chips can be used for both direct association and admixture mapping.

  6. truth MHMM HMM

  7. Ancestry of African Americans • Zakharia et al, Genome Biology, 2009 • Approximately 450,000 random SNP markers • Admixture estimation based on 7 indigenous African populations and Europeans, as well as African Americans • Principal components analysis

  8. Correlation between European IA in African Americans and PC1

  9. Ancestry Correlation in Latino Spouses (Genome Biology, 2009) Based on Ancestry Informative Markers (AIMs) in Mexican spouse pairs from Mexico City and SF Bay Area, and Puerto Rican spouse pairs from Puerto Rico and New York City.

  10. Consequences of ancestry-related assortative mating • Linkage disequilibrium (allelic associations) between unlinked loci (different chromosomes) persists at a high rate in these populations at loci which have large ancestral allele frequency differences. • Therefore, ancestry is the most important covariate in any genomic association study in these populations

  11. Population Specificity of Genetic Variation • J.A. Schneider et al, 2003 • Re-sequenced 2,036 genes (about 5 Mb) from four ethnic groups: 20 African Americans, 20 Asians, 21 Caucasians, 18 Hispanics

  12. Population Specificity of Alleles • The distribution of alleles across populations depends on the allele frequency. • Most (but not all) alleles with frequency greater than .30 are pan ethnic • Most alleles with frequency less than .10 are race-specific • Most alleles with frequency less than .02 are ethnicity specific.

  13. Global Distribution of CCR5 Δ32 mutation • Martinson et al, Nature Genetics, 1997 • Δ32 mutation confers resistance to HIV infection

  14. Global Distribution of CCR5 Δ32 mutation

  15. Irinotecan and Colon Cancer • Extreme side effects in some patients • Severe diarrhea, neutropenia • Recommended reduced starting dosage • Metabolized by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) • Homozygotes/compound heterozygotes for deficiency alleles at greatly increased risk for side effects

  16. Frequency of UGT1A1 Deficiency Genotypes by Ethnic Group

  17. Relevance • If one were to characterize genetic variation in this enzyme in Europeans only, the majority of sensitive Asians would be missed entirely.

  18. Conclusions • Genetic structure is greatest at the level of continental ancestry (correlated with race); a lower level of structure also exists at the level of ethnicity/nationality • Common genetic variants are typically pan ethnic. Low frequency variants are typically race/ethnicity specific • Low frequency variants are far more abundant than high frequency ones

  19. Conclusions • Race/ethnicity differences in disease prevalence are highly confounded between genes and environment • A group difference alone does not indicate a source for that difference

  20. Conclusions • Admixed populations (African Americans and Latino Americans) can be used to examine racial differences, but confounding may remain • Locus specific ancestry results are likely to be less confounded

  21. Conclusions • Gene-environment interactions are likely to be prominent in examining population differences • Pharmacogenetics (e.g. irinotecan) provides important examples of race/ethnicity specific genetic variation in clinical practice.

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