Meta-analysis of genome-wide association studies of stable warfarin dose in patients of African ancestry

Abstract

Warfarin dose requirements are highly variable because of clinical and genetic factors. Although genetic variants influencing warfarin dose have been identified in European and East Asian populations, more work is needed to identify African-specific genetic variants to help optimize warfarin dosing. We performed genome-wide association studies (GWASs) in 4 African cohorts from Uganda, South Africa, and Zimbabwe, totaling 989 warfarin-treated participants who reached stable dose and had international normalized ratios within therapeutic ranges. We also included 2 African American cohorts recruited by the International Warfarin Pharmacogenetics Consortium (n = 316) and the University of Alabama at Birmingham (n = 199). After the GWAS, we performed standard error-weighted meta-analyses and then conducted stepwise conditional analyses to account for known loci in chromosomes 10 and 16. The genome-wide significance threshold was set at P < 5 × 10-8. The meta-analysis, comprising 1504 participants, identified 242 significant SNPs across 3 genomic loci, with 99.6% of these located within known loci on chromosomes 10 (top SNP: rs58800757, P = 4.27 × 10-13) and 16 (top SNP: rs9925964, P = 9.97 × 10-16). Adjustment for the VKORC1 SNP -1639G>A revealed an additional locus on chromosome 2 (top SNPs rs116057875/rs115254730/rs115240773, P = 3.64 × 10-8), implicating the MALL gene, that could indirectly influence warfarin response through interactions with caveolin-1. In conclusion, we reaffirmed the importance of CYP2C9 and VKORC1 in influencing warfarin dose requirements, and identified a new locus (MALL), that still requires direct evidence of biological plausibility.