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Genetic disease treatments and pharmacogenetics: From scientific discovery to medical delivery
Date:11/14/2008

and genes that are related to dose variation requirements could be used to better estimate the proper warfarin dose based on a patient's genetic makeup, thereby reducing the risk of adverse events caused by inappropriate dosing.

McGinnis' research team were among the first to show that a polymorphism in the warfarin drug target VKORC1 accounts for a major portion (~30%) of the variance in RD, and they have recently evaluated 1,523 Swedish patients from the Warfarin Genetics (WARG) cohort in the largest study to date showing likely patient benefit from genetic forecasting of RD. In this study, the researchers found that the strongest signals were clustered around VKORC1 (the gene of the warfarin drug target), and the second strongest signals were located at SNPs clustering in the warfarin-metabolizing gene CYP2C9.

Mc Ginnis and colleagues conducted additional analyses that tested each GWAS SNP's influence on warfarin dose after adjusting for the influence of already known genetic (VKORC1, CYP2C9) and non-genetic (age, gender, etc.) factors. These analyses identified another statistical signal with genome-wide significance that corresponded to a SNP that changes the protein coding sequence of the CYP4F2 gene. This finding was confirmed in a study of 588 additional Swedish patients.

In summary, the current research results suggest that the proportion of dose variation explained by known genetic factors is approximately 29% (VKORC1), 11% (CYP2C9) and 1.5% (CYP4F2). Furthermore, by also taking into account the around 15% contribution of non-genetic factors such as age and gender, researchers can predict at least 50% of warfarin dose variation, making pre-treatment dose forecasting for individual patients a realistic possibility.

Ralph E. McGinnis, Ph.D., is a Statistical Geneticist at the Wellcome Trust Sanger Institute (Cambridge, UK) whose research focus is identifying genes and DNA variants that cause complex genetic disease or
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Contact: Kristen Long
klong@ashg.org
240-281-2386
American Society of Human Genetics
Source:Eurekalert

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