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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.

journal_name

Blood

journal_title

Blood

authors

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

doi

10.1182/blood-2014-04-568436

subject

Has Abstract

pub_date

2014-10-02 00:00:00

pages

2298-305

issue

14

eissn

0006-4971

issn

1528-0020

pii

blood-2014-04-568436

journal_volume

124

pub_type

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