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

Daneshjou R, Gamazon ER, Burkley B, Cavallari LH, Johnson JA, Klein TE, Limdi N, Hillenmeyer S, Percha B, Karczewski KJ, Langaee T, Patel SR, Bustamante CD, Altman RB, Perera MA
Blood. 2014 124 (14): 2298-305

PMID: 25079360 · PMCID: PMC4183989 · DOI:10.1182/blood-2014-04-568436

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.

© 2014 by The American Society of Hematology.

MeSH Terms (17)

African Americans Algorithms Alleles Anticoagulants Cohort Studies Exome Folic Acid Geography Haplotypes Homeostasis Humans Pharmacogenetics Phenotype Polymorphism, Single Nucleotide Quantitative Trait Loci Sequence Analysis, DNA Warfarin

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