title: Genetic risk factors for major bleeding in patients treated with warfarin in a community setting.
abstract: The influence of warfarin pharmacogenomics on major bleeding risk has been little studied in long-term users and non-specialist care settings. We conducted a case-control study to evaluate associations between CYP2C9*2/*3, VKORC1(1173), and CYP4F2*3 variants and major bleeding among patients treated with warfarin in a community setting. We calculated major bleeding odds ratios, adjusting for race, duration of warfarin use, age, gender, and body mass index. In 265 cases and 305 controls with 3.4 and 3.7 mean years of warfarin use, respectively, CYP4F2*3 was associated with decreased major bleeding risk (odds ratio: 0.62; 95% confidence interval: 0.43-0.91). CYP2C9*2/*3 and VKORC1(1173) had null associations overall, but there was a nonsignificant increase in major bleeding risk in patients with duration <6 months (odds ratio: 1.30; 95% confidence interval: 0.60-2.83; odds ratio: 1.23; 95% confidence interval: 0.57-2.64, respectively). In summary, in the largest study of warfarin pharmacogenomics and major bleeding to date, we found a 38% lower risk in patients with CYP4F2*3, potentially reflecting interaction with warfarin and dietary vitamin K intake and warranting additional evaluation.
authors: 1] Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, Washington, USA [2] Group Health Research Institute, Group Health, Seattle, Washington, USA.
authors: J A
authors: JA
authors: Roth
authors: 1] Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, Washington, USA [2] Group Health Research Institute, Group Health, Seattle, Washington, USA.
authors: D
authors: D
authors: Boudreau
authors: Group Health Research Institute, Group Health, Seattle, Washington, USA.
authors: M M
authors: MM
authors: Fujii
authors: Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington, USA.
authors: F M
authors: FM
authors: Farin
authors: Department of Medicinal Chemistry, University of Washington, Seattle, Washington, USA.
authors: A E
authors: AE
authors: Rettie
authors: 1] Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA [2] Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
authors: K E
authors: KE
authors: Thummel
authors: 1] Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle, Washington, USA [2] Institute for Public Health Genetics, University of Washington, Seattle, Washington, USA.
authors: D L
authors: DL
authors: Veenstra
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004032:Diet; D004347:Drug Interactions; D005006:Ethnicity; D005260:Female; D056726:Genetic Association Studies; D006470:Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D012307:Risk Factors; D012727:Sex Characteristics; D014859:Warfarin / Q000009:adverse effects*; D014861:Washington / Q000453:epidemiology
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C492722:CYP4F11 protein, human