Association of CYP2C9, VKORC1, CYP4F2 and EPHX1 polymorphisms in warfarin treatment related adverse events

Abstract

Warfarin is an anticoagulant, widely prescribed for prevention of thrombosis. Several polymorphisms have been found to be associated with dose requirement and other adverse effects. Four warfarin sensitive polymorphisms i.e. VKORC1, CYP2C9, EPHX1 and CYP4F2 were analysed in warfarin treated patients and these were correlated with warfarin dosage and other adverse events. Though VKORC1 and CYP2C9 are the strongest predictors of dosage and bleeding events, addition of EPHX1 and CYP4F2 showed a marginal increase in their predictive efficiency. Introduction: Warfarin, a widely prescribed anticoagulant for prevention of thrombosis, is associated with narrow therapeutic window where even small variations in dosing may result in hemorrhagic or thrombotic complications. Several polymorphisms in VKORC1, CYP2C9, CYP4F2, EPHX1, GGCX, factor IX, factor II and factor VII have been shown to be associated with warfarin dose requirement. Materials and Methods: (A) A total of 191 warfarin treated patients were genotyped for CYP2C9 and VKORC1 polymorphisms using PCR-RFLP method. (B) A total 128 warfarin treated patients were genotyped for EPHX1 T113C polymorphism using allele specific PCR method. (C) A total 107 warfarin treated patients were genotyped for CYP4F2 rs2108622:G>A polymorphism using allele specific PCR method. Results: VKORC1 variants found significantly associated with low warfarin dose requirement and risk of over anticoagulation. In CYP2C9 genotype, except CYP2C9*1/*2 all other variants were found significantly associated with low warfarin dose requirement and risk of over anticoagulation. EPHX1 and CYP4F2 polymorphisms showed moderate association with warfarin dosage but not with adverse events. Conclusion: Although the genotype of VKORC1 and CYP2C9 are clearly the most important genetic factors for warfarin response, yet inclusion of EPHX1 and CYP4F2 genotypes will be beneficial for accurate warfarin dosage in Indian patients.