The goal of this project is to apply pharmacogenomics to warfarin therapy, and gain new insights into the overall inter-individual genetic variation in response to this drug, so that prospective, individualized treatment with this anticoagulant becomes a reality. Warfarin is the most commonly employed oral anticoagulant used to treat thromboembolic disease and following surgery. One of the serious difficulties faced by physicians during both initiation of anticoagulation therapy and in determining a long-term maintenance dose is minimizing the risk of excessive bleeding. Consequently, patients have their prothrombin time (or international normalized ratio - INR) continuously monitored during the initiation phase of treatment and beyond. The ability to predict - a priori - the correct maintenance dose for an individual could be expected to revolutionize patient care and drastically cut healthcare costs. We have quantitated the effect of two critical genetic determinants of warfarin dose i.e. polymorphisms in the VKORC1 and CYP2C9 genes. Together with knowledge of patient age, sex, and concomitant drug medications, about 50% of the variability in warfarin dosing can now be accounted for in European ancestry populations, about 25% of which is due to genetic variants influencing expression of the VKORC1 gene. In this project, we propose to explore the relationship between single nucleotide polymorphisms (SNPs) in other key candidate genes and their association with warfarin maintenance dose. The long-term aim of this proposal is to account for 100% of the inter-individual variability in warfarin dosing. ? ?
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