Pharmacogenetics is the study of how genes help determine individual responses to drugs. Researchers now know that whether a standard drug regiment is effective, causes side effects, or is the appropriate dose for a given patient can depend largely on the genetic make-up of that patient. This association will make it possible, in the future, to strategically design drug therapies on an individualized basis.
Warfarin is a widely prescribed anticoagulation drug that requires intensive monitoring to heed off potentially fatal side effects. Not only does warfarin have an uncommonly narrow range of therapeutic effectiveness, there is also great variation in dosing requirements. These factors lead to a complicated course in deriving the appropriate dose for each patient. They also suggest that genetic variation likely influences the way the body responds to warfarin therapy.
Jeffrey L. Anderson, M.D. and his colleagues at the University of Utah School of Medicine reported, in the December issue of Journal of Thrombosis and Thrombolysis, that there are specific genetic causes for much of the variation seen in patients taking warfarin. The authors speculated that differences in two genes essential for warfarin metabolism (CYP2C9, which encodes an enzyme required for the metabolism of about 80% of drugs) and activity (VKORC1, which encodes a member of the Vitamin K pathway) would be responsible for individual variation in dosing requirements.
For each of over 200 patients, the stable daily maintenance dose of warfarin was established and the sequence of the two genes, or the genotype, was determined. The authors found that relative to the most common genotype for CYP2C9, patients with any of three common variant genotypes had significantly lower warfarin dose requirements (reduced from 18-72% depending on the genotype). Similarly, carrying either of the two VKORC1 variants reduced warfarin dose by 36-45% (Carlquist et al. 2007 J Thromb Thrombolysis 22(3)).
Diet, age, and weight are known to influence warfarin dosing, but are only weakly associated and at best account for about 12% of variation in responses. Strikingly, the gene differences reported in this study account for ~33%. There are likely to be additional genes and variants that also impact warfarin metabolism, making the genetic component the dominant known factor in warfarin response. A larger-scale prospective study and wider availability of sequencing technology would allow physicians to consider the pharmacogenetic status of individuals before prescribing oral anticoagulation treatment in the future.
A new test was recently released to predict excessive bleeding risks among patients who take warfarin, which is the most frequently prescribed oral anticoagulant used for the prevention and treatment of thromboembolic events. Warfarin is a difficult drug to manage due to its narrow therapeutic range and inconsistent patient response resulting from inter-individual variability.
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