The pharmacogenetics of warfarin in clinical practice

Abstract

Warfarin is the most widely prescribed oral anticoagulant. It shows great (up to 20-fold) interindividual variability in dose requirement because of both, genetic and environmental factors. Information from pharmacogenomics, a study of the interaction of the individual's genotype and drug response, can help optimize drug efficacy and minimize adverse drug reactions. Genotyping data on two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 (VKORC1), confirmed their influence on warfarin maintenance dose. Genome-wide association study also found a weak effect of CYP4F2. The presence of CYP2C9*2 or CYP2C9*3 variant alleles, which results in decreased enzyme activity, is associated with a signi cant decrease in the mean warfarin dose. VKORC1 single nucleotide polymorphisms (SNPs)explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold CYP2C9 effect. Carrier state of a combination of VKORC1 and CYP2C9 polymorphisms, rather than of one of these polymorphisms is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype. Warfarin resistance has been related to several missense mutations in the VKORC1. Algorithms incorporating genetic (CYP2C9 and VKORC1), demographic, and clinical factors to estimate warfarin dosage could potentially minimize the risk of overdose during warfarin induction.