Pharmacogenetics of target genes across the warfarin pharmacological pathway.
Warfarin is a widely prescribed anticoagulant for thromboembolic disorders and exhibits wide inter-individual differences in its pharmacodynamic effects. Warfarin exerts its anticoagulant effect by inhibiting the enzymatic activity of vitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) which regenerates reduced vitamin K as an essential cofactor for the post-translational gamma-carboxylation of glutamic acid residues on coagulation factors II, VII, IX and X, and the anticoagulant proteins C, S and Z. Recent studies have shown polymorphisms in genes involved in the uptake of vitamin K (apolipoprotein E [ApoE]), reduction of vitamin K 2,3-epoxide (VKORC1), metabolism of warfarin (cytochrome P450 2C9 [CYP2C9]), and gamma carboxylation (gamma-glutamyl carboxylase [GGCX]) to influence the pharmacokinetics and pharmacodynamics of warfarin in patients from different ethnic backgrounds, resulting in variable warfarin dose requirements. Understanding the causal relationship of these polygenic influences on warfarin dose requirements in patients of different ethnicity may be vital in reducing inter-patient variability and optimising anticoagulant therapy.
Lal
Suman
S
National Cancer Centre, Laboratory of Clinical Pharmacology, Division of Medical Sciences, Singapore, Singapore.
Jada
Srinivasa Rao
SR
Xiang
Xiaoqiang
X
Lim
Wan-Teck
WT
Lee
Edmund J D
EJ
Chowbay
Balram
B
D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000235:genetics / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology*
D000925:Anticoagulants; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; 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; D004851:Epoxide Hydrolases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase