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Vanderbilt Study Finds Genes Impact Response to Blood Thinner Warfarin

Mar. 5, 2008, 4:13 PM

Variations in a gene involved in blood clotting determine patients’ initial response to the common blood thinner warfarin, researchers at Vanderbilt University Medical Center have reported.

The finding, published in this week’s New England Journal of Medicine, could help doctors determine the optimal dose of warfarin more quickly and precisely through genetic screening, and could reduce the incidence of side effects from the drug, particularly severe bleeding.

An estimated 2 million people in the United States take warfarin, also known as Coumadin, to prevent blood clots after a heart attack, stroke or major surgery. Because patients’ responses to the drug vary widely, it’s difficult at the beginning of therapy

Scientists have known for several years that variations in two genes affect patients’ response to warfarin. One gene, CYP2CP, codes for an enzyme that breaks down warfarin in the body. The other, VKORC1, encodes the enzyme that warfarin blocks in order to prevent clot formation. What was not known was the relative impact of these genetic variants when warfarin was first given.

“Our study showed that during the first weeks of warfarin therapy, variation in the VKORC1 gene is a more important contributor to sensitivity to warfarin than variation in the CYP2C9 gene,” said the study’s senior author, C. Michael Stein, M.B., Ch.B., associate chief of Clinical Pharmacology.

The findings exemplify the potential value of pharmacogenomics, the study of how genetic variation affects individual responses to medication, said Dan Roden, M.D., vice chancellor for Personalized Medicine, who contributed to the study.

“We’re really at the cusp of an entirely new era where genotypes will be available in some way, rapidly, and the fact that we don’t know exactly how to use all of those things right now is not surprising,” said Roden.

Last year the U.S. Food and Drug Administration (FDA) updated labeling for warfarin to notify doctors that genetic testing could help improve their estimates for the initial dosages needed by their patients.

“This is the fifth or sixth example of a drug that has had its label changed in the last two years based on the notion that there are genetic determinants of response,” Roden said. “Warfarin is probably the first example of a widely used drug where we’re predicting variability in a large chunk of the population, and the variability may make a difference in outcome.”

A study by the FDA’s Office of Policy and Planning estimated that genetic testing could avoid 85,000 serious bleeding events and 17,000 strokes associated with warfarin treatment each year, and reduce the annual cost of treating these adverse events by more than $1 billion.

Further studies are needed to determine whether genetic testing will actually yield such benefits, Stein and Roden cautioned.

Many factors can affect patients’ response to warfarin, including other diseases and other drugs they are taking. And while variants of the CYP2CP gene played a minor role in determining response when therapy was started, in some patients or in combination with other genetic variations, they may be exceedingly important.

This will take a lot of work to sort out, “but we’re very well positioned here to do that,” Roden said. Efforts at Vanderbilt include the DNA Database resource, an anonymous databank launched last year to link genetic and clinical information in a way that can help answer questions about drug effects and disease.

“The ultimate goal is to have these kinds of data available at the time of prescription,” he said. “Imagine a day when we can get your whole genome sequenced fast and cheap. It might even become part of neonatal testing.”

Co-authors of the study were Ute Schwarz, M.D., and Richard Kim, M.D., now at the University of Western Ontario and the Lawson Health Research Institute in London, Ontario, Canada; and Marylyn Ritchie, Ph.D., Yuki Bradford, Chun Li, Ph.D., Scott Dudek and Amy Frye-Anderson, R.N., at Vanderbilt.

The study was supported by the National Heart, Lung, and Blood Institute, the National Institute of General Medical Sciences, and the NIH-funded Pharmacogenetics Research Network.

— when the risk of complications is highest — to find the dose that will prevent clotting without causing serious bleeding, for example, in the gastrointestinal tract or the brain.

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