Genetic variant in folate homeostasis is associated with lower warfarin dose in African Americans

Abstract

The anticoagulant warfarin has >30 million prescriptions per year in the United States. Doses can vary 20-fold between patients, and incorrect dosing can result in serious adverse events. Variation in warfarin pharmacokinetic and pharmacodynamic genes, such as CYP2C9 and VKORC1, do not fully explain the dose variability in African Americans. To identify additional genetic contributors to warfarin dose, we exome sequenced 103 African Americans on stable doses of warfarin at extremes (≤ 35 and ≥ 49 mg/week). We found an association between lower warfarin dose and a population-specific regulatory variant, rs7856096 (P = 1.82 × 10(-8), minor allele frequency = 20.4%), in the folate homeostasis gene folylpolyglutamate synthase (FPGS). We replicated this association in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum (P = .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P = 3.93 × 10(-5)) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P = .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N = 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response.

Figure 1

Manhattan plot of discovery cohort. Bonferroni cutoff of 3.22 × 10⁻⁷ for significance. The 2 top SNPs are in LD and are in FPGS.

Figure 2

QQ-plot of expected and observed P values.

Figure 3

Distribution of associated risk allele across diverse populations. The risk allele, which is the ancestral allele, is most prevalent on the African continent. Map generated using Human Genome Diversity Project (HGDP) data through the HGDP Selection Browser.^,

Figure 4

Effect of SNP on FPGS expression in LCLs across 3 African populations (MKK, LWK, and YRI). Effect on expression was evaluated using a linear model with population and rs7856096 (modeled additively) as covariates.