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

Abstract

Key Points• A population-specific genetic variant involved in folate homeostasis is associated with lower warfarin dose in African Americans.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 5 1.82 3 10 28 , minor allele frequency 5 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 5 .046). In a combined cohort, adding rs7856096 to the International Warfarin Pharmacogenetic Consortium pharmacogenetic dosing algorithm resulted in a 5.8 mg/week (P 5 3.93 3 10 25 ) decrease in warfarin dose for each allele carried. The variant overlaps functional elements and was associated (P 5 .01) with FPGS gene expression in lymphoblastoid cell lines derived from combined HapMap African populations (N 5 326). Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response. (Blood. 2014;124(14):2298-2305

Oral anticoagulation: a critique of recent advances and controversies

“…First, a GWAS in African-Americans showed that a SNP in the CYP2C gene cluster (rs12777823) independently of CYP2C9*2 and CYP2C9*3 also influenced warfarin dose requirement, improving the variability explained by the IWPC algorithm by 21% [43]. Second, an exome sequencing study in African-American patients on extremes of doses showed that individuals with a variant allele in folylpolyglutamate synthase (FPGS) (rs7856096) required lower doses [44]. Consistent with this, an ethnicity-specific algorithm performed better than the original IWPC algorithm in a recent study [45].…”

Strategies for Equitable Pharmacogenomic-Guided Warfarin Dosing Among European and African American Individuals in a Clinical Population

“…7 There are also variants important for dosing among individuals of African descent alleles that were unaccounted for in these trials. 7–11 Drozda found that failing to take into account these expanded variants resulted in significantly worse dose predictions among African Americans. 12 Additionally, Limdi found that using a race stratified dosing approach resulted in significantly more dose variation explained in both whites and blacks compared to a race-combined dosing model.…”

Genotype-based clinical trials in cardiovascular disease

“…However, with the advent of more-expensive, ‘next-generation’ sequencing technology, extreme drug-response phenotypes—defined typically as those individuals with drug response ≤5 th percentile, or ≥95 th percentile—are more commonly used to identify novel pharmacogenetic markers (for example, in warfarin dosing). 18 …”