Pharmacogenetics of warfarin: current status and future challenges

doi:doi:10.1038/sj.tpj.6500417

Abstract

Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P₄₅₀ 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

Keywords:

warfarin, vitamin K epoxide reductase complex subunit 1, VKORC1, cytochrome P450 enzyme, CYP2C9, vitamin K-dependent protein

Abbreviations:

ABCB1, ATP-binding cassette transporter B1 gene, P-glycoprotein gene or MDR1; APOE, apolipoprotein E gene; CALU, calumenin gene; CAR, constitutive androstane receptor; CYP1A1, cytochrome P₄₅₀ 1A1 gene; CYP1A2, cytochrome P₄₅₀ 1A2 gene; CYP2A6, cytochrome P₄₅₀ 2A6 gene; CYP2C18, cytochrome P₄₅₀ 2C18 gene; CYP2C19, cytochrome P₄₅₀ 2C19 gene; CYP2C8, cytochrome P₄₅₀ 2C8 gene; CYP2C9, cytochrome P₄₅₀ 2C9 gene; CYP3A4, cytochrome P₄₅₀ 3A4 gene; CYP3A5, cytochrome P₄₅₀ 3A5 gene; EPHX1, epoxide hydrolase 1, microsomal gene; F2, coagulation factor II gene or prothrombin gene; F5, coagulation factor V gene; F7, coagulation factor VII gene; F9, coagulation factor IX gene; F10, coagulation factor X gene; FII, coagulation factor II or prothrombin; FIIa, coagulation factor II activated or thrombin; FIX, coagulation factor IX; FIXa, coagulation factor IX activated; FV, coagulation factor V; FVII, coagulation factor VII; FVIIa, coagulation factor VII activated; FX, coagulation factor X; FXa, coagulation factor X activated; GAS6, growth-arrest-specific 6 gene; GGCX, gamma-glutamyl carboxylase gene; MDR1, multidrug resistance gene 1, P-glycoprotein gene or ABCB1; NQO1, NAD(P)H dehydrogenase, quinone 1 gene; NR1I2, pregnane X receptor gene; NR1I3, constitutive androstane receptor gene; ORM1, orosomucoid 1 gene or alpha-1-acid glycoprotein 1 gene; ORM2, orosomucoid 2 gene or alpha-1-acid glycoprotein 2 gene; PROC, protein C gene; PROS1, protein S gene; PROZ, protein Z gene; PT INR, prothrombin time international normalized ratio; PXR, pregnane X receptor; SERPINC1, anti-thrombin III gene; SNP, single nucleotide polymorphism; VKORC1, vitamin K epoxide reductase complex subunit 1 gene

Review