R. Daneshjou,1 E. R. Gamazon,2 B. Burkley,3 L. H. Cavallari,3 J. A. Johnson,3 T. E. Klein,1 N. Limdi,4 S. Hillenmeyer,1 B. Percha,1 K. J. Karczewski,1 T. Langaee,3 S. R. Patel,5 C. D. Bustamante,1 R. B. Altman,1 M. A. Perera2; 1Stanford University, Stanford, CA, 2University of Chicago, Chicago, IL, 3University of Florida, Gainesville, FL, 4University of Alabama, Birmingham, AL, 5University of Illinois, Chicago, IL
BACKGROUND: 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. In this study, we sought to discover novel associations between genetic factors in African Americans and warfarin dose.
METHODS: 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 replicated our findings in an independent cohort of 372 African American subjects whose stable warfarin doses represented the full dosing spectrum.
RESULTS: 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) and replicated this association in (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).
CONCLUSION: Our results provide the first evidence linking genetic variation in folate homeostasis to warfarin response.