Genes could explain the dose of Warfarin

A newly discovered gene involved in blood clotting may make take some of the guesswork out of the complicated dosing issues with the anticoagulant drug warfarin (Coumadin).

About 2 million people take warfarin to prevent dangerous clotting after a heart attack, stroke or surgery. The proper dose of the drug varies from patient to patient and is often hard to predict. Now, researchers from the University of Washington in Seattle and Washington University in St. Louis have uncovered a gene that may play a role in the variability related to the drug.

Researchers conducted a retrospective study of 186 European-American patients on long-term warfarin maintenance therapy. By looking at the genetic makeup of these patients, researchers learned that variations in a specific blood-clotting gene could explain why some people need a lower or higher dose of the drug to get its full benefits.

Typically, doctors use information about a patient’s sex, age, weight and medical history to determine the initial dose of warfarin to be used. But the ideal dose for a patient is often not determined until after several follow-up visits and blood tests. Allan E. Rettie, Ph.D., from the University of Washington, says: “There is a narrow window between too much and too little effect. A small change in dose can have quite a large effect on blood processes.” He explains that a dose that’s too high can lead to excessive bleeding while a dose that’s too low could let dangerous blood clots form.

Rettie and colleagues focused on the gene vitamin K epoxide reductase complex 1 (VKORC1), which makes a protein that helps control clotting and is the key target of warfarin. Researchers analyzed the VKORC1 gene’s DNA sequence in patients who were on a stabilized dose of warfarin. They searched for common DNA variations responsible for changing the gene’s activity and the amount of protein it made.

Rettie says, “We found that 25 percent of the [overall] variance in warfarin dose is due to this one gene. This is possibly the single biggest contributor to variability in people’s responses to the drug and could be a central factor in setting the initial dose.”

SOURCE: The New England Journal of Medicine, 2005;352:2285-2293

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