Abstract TP518: Ethnic Differences in Poor Metabolizer Alleles of 12 Pharmacogenomic Actionable Genes in Asian Indians

Introduction: Diversity in drug response related to cardiovascular and other diseases is attributed to both genetic and non-genetic factors. However, there is a paucity of genetic information across ethnically and genetically diverse populations. Here, we have analyzed 20 SNPs from 12 pharmacogenomics genes in Punjabi Sikhs of Asian Indian origin (N= 1,616), as part of the Sikh Diabetes Study (SDS)/Asian Indian Diabetic Heart Study (AIDHS). Methods: Samples were genotyped using the Human 660W Quad Bead Chip panel (Illumina, Valencia, CA). We compared the allelic associations with poor metabolism (PM) phenotype across other HapMap populations. Results: Indians had a significantly higher frequency of CYP2C9*3 (12% SDS, 13% GIH (Gujarati Indians) vs. 5% in Europeans (CEU) (p genotype = 0.008) and ‘T’ allele of CYP4F2 (36%) SDS, (43%) GIH vs. (21%) in CEU (p genotype =7.8x10 -7 ); both associated with a higher risk of bleeding with warfarin. The PM phenotype of the CYP1A2*1F allele for slow metabolism of caffeine and carcinogens was significantly higher in Indians (SDS 43%, GIH 51%) compared to CEU 29% (p genotype =0.01). While the frequency of ‘T’ risk allele MTHFR (C677T) was significantly lower in Indians compared to Europeans (0.19 SDS, 0.16 GIH vs. 0.31 CEU), the low activity ‘C’ allele of MTHFR was strikingly higher in SDS (44%) compared to GIH (39%) and CEU (34%) (p genotype =4.9x10 -3 ). These variants in MTHFR affect the metabolism of cholesterol-lowering (statins), 5-fluorouracil, and methotrexate-based cancer drugs. Conclusion: This is a first large study reporting a significant ethnic difference in the frequency of PM phenotype in Indian Sikhs compared to other global populations. Our findings underscore the need for establishing a global benchmark by conducting pre-emptive genotyping in drug metabolizing genes before beginning therapeutic intervention.