Pharmacogenomics of anticoagulants: steps toward personal dosage.
Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application.
Institute of Cellular Medicine, Newcastle University Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Ann K
AK
Daly