title: Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin.
abstract: The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways.
authors.affiliation: Section of Cardiology, Heart & Vascular Center, Lebanon, New Hampshire 03756, USA. erik.fung@hitchcock.org
authors.forename: Erik
authors.initials: E
authors.lastname: Fung
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Steven M
authors.initials: SM
authors.lastname: Belknap
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Rourke
authors.forename: John F
authors.initials: JF
authors.lastname: Robb
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Shworak
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019934:International Normalized Ratio; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: 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