Genome-wide association scan reveals the landscape of inherited variability in response to warfarin dose
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 per cent 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 1000 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 per cent of the dose variability) and the major effects of VKORC1 (~30 per cent) and CYP2C9 (~12 per cent). 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.
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Participating Centres
- Wellcome Trust Sanger Institute, Hinxton, United Kingdom
- Clinical Pharmacology, Karolinska Institute, Campus Huddinge, Stockholm, Sweden
- Department of Medical Sciences, Clinical Pharmacology, University Hospital, Uppsala, Sweden
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The Wellcome Trust Sanger Institute
The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.
The Wellcome Trust
The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.
