Genetic influences on the response to warfarin.
OBJECTIVE
Warfarin has a narrow therapeutic index and there is wide interindividual variability in the drug dose requirement. Uncertainty of response renders currently used loading regimens inaccurate as they fail to take into account individual patient factors that have a major influence on anticoagulation response. This review focuses on recent research findings demonstrating the impact of genetics on warfarin sensitivity and dose requirement and the issues concerning the clinical utility of individualized therapy.


RESULTS
Single-nucleotide polymorphisms in cytochrome P450 2C9 and vitamin K epoxide reductase have been shown to make significant contributions to the variability in warfarin dose requirements. Polymorphisms in other genes that mediate the actions of warfarin make little or no contribution to the variability. Racial and cultural differences influence dose requirements, which can be explained at least in part by genetic and dietary factors.


CONCLUSIONS
Individualization of therapy based on genetic and environmental factors has the potential to reduce the adverse effects associated with the commencement of warfarin therapy. Prospective studies that incorporate both CYP2C9 and VKORC1 genes and environmental factors in warfarin dose calculation will be required to demonstrate the safety, cost-effectiveness, and feasibility of individualized dosing regimens.
Kamali
Farhad
F
School of Clinical and Laboratory Sciences, Wolfson Unit of Clinical Pharmacology, Claremont Place, University of Newcastle, Newcastle upon Tyne, UK. farhad.kamali@ncl.ac.uk
D000925:Anticoagulants / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics*; D002986:Clinical Trials as Topic; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D006899:Mixed Function Oxygenases / Q000187:drug effects / Q000235:genetics*; D010597:Pharmacogenetics; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*
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