Abstract 15518: Novel SNPs Associated with Warfarin Dose in a Large Multicenter Cohort of African Americans: Genome Wide Association Study and Replication Results
Warfarin has consistently shown large interindividual differences in therapeutic dose and has a high potential for adverse events due to over and under-dosing. Several genome wide association studies (GWAs) in predominantly Caucasian cohorts, have found VKORC1 and CYP2C9 are the major genes associated with stable warfarin dose. These same SNPs explain a much lower proportion of dose variability in African Americans, leading to the hypothesis that African-specific genetic variation may explain more of the variability in warfarin dose in this population. To identify these variants, we performed a multicenter GWAs meta-analysis, on 546 African Americans on stable warfarin therapy. Subjects were genotyped on either the Illumina Human1M-Duo 3.0 or the Illumina 610 Quad BeadChip array with imputation to phased HapMap II data, resulting in approximately 3 million SNPs. After accounting for covariates known to influence warfarin dose: age, weight, height, aspirin and amiodarone use, the strongest association signal was at the known VKORC1-1639 polymorphism, (rs9923231 p = 2 x 10-9). SNPs on chromosome 2 (rs9341106) and 10 (rs12777823, rs2104162) were also significant. We then conditioned on the known SNPs in both VKORC1 (-1639) and CYP2C9 (CYP2C9*2 and *3). A genome-wide significant signal remained on chromosome 10 at the CYP2C locus. This SNP (rs12777823, p = 1 x 10-8) is upstream of CYP2C18 with a minor allele frequency of 0.26, and is not in linkage disequilibrium with any of the previously associated CYP2C9 coding SNPs including those specific to African Americans (CYP2C9*8, *11, *5 and *6). This SNP explained an additional 5% of warfarin dose variation in African Americans. This finding was replicated in an independent cohort of 82 African Americans (rs12777823, p = 0.02). A larger replication in 350 African Americans is ongoing. In conclusion, we have performed the first and largest warfarin GWAs in African Americans and have found novel variation significantly associated with stable warfarin dose. This GWAs is the first to identify variation outside VKORC1 or CYP2C9 that explains additional variation in dose. These findings have far reaching applications in providing clinically useful pharmacogenetic information in diverse clinical settings.
- © 2011 by American Heart Association, Inc.