Influence Of CYP2C9*3, VKORC1-1639G>A And CYP4F2rs2108622Genotypes On The Risk Of Hemorrhagic Complications In Warfarin-treated Patients

[Objective] To investigate the influence of the warfarindose-associated genotypes, cytochrome P450, family2, subfamily C,polypeptide9(CYP2C9*3), vitamin K epoxide reductase complex, subunit1(VKORC1-1639G>A), and cytochrome P450, family4, subfamily F,polypeptide2(CYP4F2rs2108622) gene polymorphisms on the risk ofhemorrhagic complications in warfarin-treated patients after undergoingheart valve replacement.[Methods] From January2011to August2013, patients who were operatedin the Department of Cardiovascular Surgery of Fujian Provincial Hospitalwere enrolled in this study. Genomic DNA was extracted from the peripheralblood from the patients. CYP2C9*3, VKORC1-1639G> A and CYP4F2rs2108622genotypes of patients were detected by using the method of PolymeraseChain Reaction（PCR）-gene sequencing. The association between thewarfarin dose-associated genotypes and over-anticoagulation orhemorrhagic complications was evaluated by Cox proportional hazardregression using SPSS Statistics19.0.[Resμlts]18major hemorrhages and59minor hemorrhages occurred over434person-years among196patients (50.8±10.7years,40.8%men) withan average of26.9(±11.8) months of follow-up accrued. For CYP2C9*3genotype, AC alleles conferred an increased risk for over-anticoagulationwith international normalization ratio (INR)＞4[hazard ratio (HR)7.10;95%confidence interval (CI):2.54-19.79], but not hemorrhage (HR0.29;95%CI:0.12-137.21). For VKORC1-1639G> A genotype, AA alleles conferredan increased risk for total hemorrhage (HR3.14;95%CI:1.14-8.68), butnot over-anticoagμlation (HR2.45;95%CI:0.79-7.63), minor (HR2.81; 95%CI:0.80-9.93) or major hemorrhage (HR4.59;95%CI:0.86-24.48). Thevariant CYP4F2rs2108622genotype did not confer significant increase inrisk for hemorrhage (HR0.89;95%CI:0.43-1.82) or over-anticoagulation(HR0.43;95%CI:0.16-1.13). For VKORC1-1639G>A genotype, Kaplan-Meiercurves showed that time to total hemorrhagic events was significantlyshorter for patients with AA alleles than those with the GG and GA alleles(log-rank test, P=0.03), but not for patients with CYP2C9*3or CYP4F2rs2108622genotype (P=0.17and0.80).[Conclusion] The CYP2C9*3heterozygous mutants carriers had anincreased risk of over-anticoagμlation yet whose risk of bleeding eventsdid not increase. The variant VKORC1-1639G>A homozygous mutants carriershad an increased risk of hemorrhagic complications. No significantassociation was found between CYP4F2rs2108622genotype andover-anticoagulation or hemorrhagic complications. VKORC1-1639G>A maybe the main genetic factor in hemorrhagic complications in Chinesepatients under warfarin anticoagμlation.