Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives.
Warfarin is the most widely prescribed oral anticoagulant, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response. Information from pharmacogenomics, the study of the interaction of an individual's genotype and drug response, can help optimize drug efficacy while minimizing adverse drug reactions. Pharmacogenetic analysis of 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. Possession of CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, is associated with a significant decrease in the mean warfarin dose. Several single nucleotide polymorphisms (SNPs) in VKORC1 are associated with warfarin dose across the normal dose range. Haplotypes based on these SNPs explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold greater effect than CYP2C9. Algorithms incorporating genetic (CYP2C9 and VKORC1), demographic, and clinical factors to estimate the warfarin dosage, could potentially minimize the risk of over dose during warfarin induction.
Yin
Tong
T
National Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Miyata
Toshiyuki
T
D000483:Alleles; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects* / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D006899:Mixed Function Oxygenases / Q000187:drug effects* / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases