Genes determining the optimal dose of therapeutic warfarin have now been identified in a large-scale, genome-wide association scan (GWAS) of this pharmacogenetic trait. Researchers from the Wellcome Trust Sanger Institute, Uppsala University Hospital, and the Karolinska Institute have found common sequence variants in three genes – VKORC1, CYP2C9 and CYP4F2 – that explain over 40% of the variability in the warfarin dose needed to achieve proper blood thinning. The study, published March 20 in the open-access journal PLoS Genetics, assayed more than 1,000 warfarin patients at approximately 370,000 chromosomal variants densely covering the human genome.
Warfarin is a widely prescribed anticoagulant, administered to reduce the risk of stroke, deep vein thrombosis, pulmonary embolism and heart attack in high-risk patients. However, patients vary widely (20-fold) in the warfarin dose needed, meaning that initial doses in some patients are too high (risking severe bleeding) or too low (risking serious illness). Identification of genetic factors causing dose variation could now be used to more accurately forecast the required warfarin dose and thereby reduce patient risk.
The statistical techniques and large GWAS sample enabled detection of the minor effect of CYP4F2 (explaining ~1.5% of the dose variability) and the major effects of VKORC1 (~30%) and CYP2C9 (~12%). Together, these results provide the first comprehensive overview of the genetic landscape influencing variability in warfarin dosage.
The study concludes that clinical trials of dose forecasting based on VKORC1 and CYP2C9 (with the possible inclusion of CYP4F2) are likely to provide state-of-the-art clinical benchmarks for warfarin use in the foreseeable future. Future studies could also expand the search to identify the genetic determinants of life-threatening bleeding, a rare adverse reaction to warfarin treatment.
CITATION: Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, et al. (2009) A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. PLoS Genet 5(3): e1000433. doi:10.1371/journal.pgen.1000433
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PLoS Genetics