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Pharmacogenetics of Target Genes Across the Warfarin Pharmacological Pathway

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Abstract

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 γ-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 (γ-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.

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Acknowledgements

This review was supported by a grant from Singapore Cancer Syndicate (PS0023). The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Laboratory of Clinical Pharmacology, Division of Medical Sciences, National Cancer Centre, Singapore, Singapore

    Suman Lal, Srinivasa Rao Jada, Xiaoqiang Xiang &  Balram Chowbay

  2. Department of Medical Oncology, National Cancer Centre, Singapore, Singapore

    Wan-Teck Lim

  3. Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore, Singapore

    Edmund J. D. Lee

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  1. Suman Lal
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Lal, S., Jada, S.R., Xiang, X. et al. Pharmacogenetics of Target Genes Across the Warfarin Pharmacological Pathway. Clin Pharmacokinet 45, 1189–1200 (2006). https://doi.org/10.2165/00003088-200645120-00004

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