Warfarin pharmacogenomics

Abstract

Warfarin therapy is complicated by a narrow therapeutic index and substantial interpatient variability in dose response. The cytochrome P450 (CYP)2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genes have recently been determined to be associated with warfarin dose requirements, with reduced doses of this drug being required in patients with the variant CYP2C9*2, CYP2C9*3, or VKORC1 -1639A allele. The combination of genotype and clinical factors explains approximately 50 to 60% of the variance in warfarin dose requirements in Caucasians and Asians, but only 25 to 40% among African Americans. Racial differences in the association between genotype and a patient's response to warfarin treatment may be caused by racial differences in the frequencies of the variant CYP2C9*2, CYP2C9*3, and VKORC1 -1639A alleles or by the influence of non-genetic factors. Genotype also influences the time required to attain therapeutic anticoagulation and the risk for over-anticoagulation and hemorrhage. Although the incorporation of genotype information improves the accuracy of dose prediction, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been demonstrated. Therefore, the routine use of CYP2C9 and VKORC1 genotyping is not supported by currently available evidence. The results of ongoing or future multicenter clinical trials are expected to clarify the role of pharmacogenomics in the management of warfarin therapy.