title: Race influences warfarin dose changes associated with genetic factors.
abstract: Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race.
authors.affiliation: Department of Neurology and.
authors.forename: Nita A
authors.initials: NA
authors.lastname: Limdi
authors.affiliation: Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL;
authors.forename: Todd M
authors.initials: TM
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA;
authors.forename: Qi
authors.initials: Q
authors.lastname: Yan
authors.affiliation: Department of Clinical and Administrative Sciences, Notre Dame of Maryland University School of Pharmacy, Baltimore, MD;
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Thigpen
authors.affiliation: Department of Epidemiology and.
authors.forename: Aditi
authors.initials: A
authors.lastname: Shendre
authors.affiliation: Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL; and.
authors.forename: Nianjun
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hill
authors.affiliation: Department of Epidemiology and.
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.affiliation: Department of Biostatistics, Section on Statistical Genetics, University of Alabama at Birmingham, Birmingham, AL; and.
authors.forename: T Mark
authors.initials: TM
authors.lastname: Beasley
mesh_terms: D001741:Black or African American / Q000235:genetics; D000465:Algorithms; D000925:Anticoagulants / Q000008:administration & dosage; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D044469:Racial Groups / Q000235:genetics*; D012044:Regression Analysis; D051436:Renal Insufficiency, Chronic; D054556:Venous Thromboembolism / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000008:administration & dosage*; D044465:White People / Q000235:genetics
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases