title: Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin.
abstract: This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 -1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1 year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3 months. CYP2C9*3, VKORC1 -1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95 % confidence interval (CI) 1.57-6.01] and minor hemorrhage (HR 3.28, 95 % CI 1.62-6.65), but not major hemorrhage (HR 0.44, 95 % CI 0.04-4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) ≥4 (HR 2.92, 95 % CI 1.08-7.85). VKORC1 -1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan-Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (P = 0.001), but not for patients with VKORC1 -1639 G/A or CYP4F2 rs2108622 genotype (P = 0.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation.
authors.affiliation: Institute of Geriatric Cardiology, General Hospital of Chinese People's Liberation Army, No. 28 Fu Xing Road, Beijing, 100853, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Caiyi
authors.initials: C
authors.lastname: Lu
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D002681:China / Q000453:epidemiology; D065729:Cytochrome P-450 CYP2C9; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004790:Enzyme Induction; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000208:ethnology; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D019934:International Normalized Ratio; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012306:Risk; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000925:Anticoagulants; D065607:Cytochrome P-450 Enzyme Inhibitors; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases