Scientists have identified which variations of a specific gene determine a patient's initial response to treatment with the blood-thinning (anticoagulant) drug warfarin. Researchers with the National Institutes of Health (NIH) Pharmacogenetics Research Network found that the gene VKORC1 plays a major role in determining a patient's initial sensitivity to warfarin treatment -- when dosage amounts are most critical to prevent clotting problems in patients.
Researchers assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3) and VKORC1 haplotypes (designated A and nonA) in 297 patients starting warfarin therapy. They compared the participants' clinical characteristics and response to therapy, determined by international normalized ratio (INR) and bleeding events. Their findings confirm earlier research that the two genes, VKORC1 and CYP2C9, help predict how well a patient responds to warfarin. The new results take scientists' understanding a step further and indicate that although both genes significantly influence response to the drug after the first two weeks of therapy, only variations of VKORC1 predict response within the first week of therapy.
The blood clotting variations in VKORC1 help explain why certain patients require a lower or higher dose of warfarin to get its full benefits. The findings could ultimately help doctors determine a patient's optimal warfarin dose more quickly and precisely through genetic screening for the VKORC1 gene and could result in better warfarin dosing, thereby increasing the safety and effectiveness of treatment.
After the discovery of the two genes that play a role in warfarin responsiveness, the Food and Drug Administration (FDA) approved labeling changes in August 2007 instructing physicians to use genetic testing when determining initial dosage estimates for their patients. However, until now, information on genetic interactions with initial response to therapy was limited.
An estimated 2 million people in the United States take the anticoagulant drug warfarin to prevent harmful clotting after a heart attack, stroke, or major surgery. Despite its wide use, physicians find the drug challenging to prescribe because individuals' responses vary widely, and too high of a dose can result in excessive bleeding while too low a dose could allow dangerous blood clots to form.
The study was conducted by researchers at Vanderbilt University and funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of General Medical Sciences (NIGMS), both part of NIH.
The article, "Genetic Determinants of Initial Warfarin Response," is published in the March 6, 2008, issue of the New England Journal of Medicine. An accompanying editorial written by NHLBI Director Elizabeth G. Nabel, M.D., and NHLBI Deputy Director Susan B. Shurin, M.D., on the role of pharmacogenomics is also in the NEJM.
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