title: 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.
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA;
authors: Roxana
authors: http://orcid.org/0000-0001-7988-9356
authors: R
authors: Daneshjou
authors: Department of Medicine, University of Chicago, Chicago, IL;
authors: Eric R
authors: http://orcid.org/0000-0003-4204-8734
authors: ER
authors: Gamazon
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL;
authors: Ben
authors: B
authors: Burkley
authors: Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL;
authors: Larisa H
authors: LH
authors: Cavallari
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL;
authors: Julie A
authors: JA
authors: Johnson
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA;
authors: Teri E
authors: TE
authors: Klein
authors: Department of Neurology and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL; and.
authors: Nita
authors: N
authors: Limdi
authors: Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, CA.
authors: Sara
authors: S
authors: Hillenmeyer
authors: Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, CA.
authors: Bethany
authors: B
authors: Percha
authors: Biomedical Informatics Training Program, Stanford University School of Medicine, Stanford, CA.
authors: Konrad J
authors: KJ
authors: Karczewski
authors: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL;
authors: Taimour
authors: T
authors: Langaee
authors: Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL;
authors: Shitalben R
authors: SR
authors: Patel
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA;
authors: Carlos D
authors: CD
authors: Bustamante
authors: Department of Genetics, Stanford University School of Medicine, Stanford, CA;
authors: Russ B
authors: RB
authors: Altman
authors: Department of Medicine, University of Chicago, Chicago, IL;
authors: Minoli A
authors: MA
authors: Perera
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D015331:Cohort Studies; D059472:Exome; D005492:Folic Acid / Q000378:metabolism*; D005843:Geography; D006239:Haplotypes; D006706:Homeostasis; D006801:Humans; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D005492:Folic Acid