Gene May Affect Blood-Clot Drug's Effects

Testing could one day help doctors prescribe the best dose, study says

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HealthDay Reporter

WEDNESDAY, June 1, 2005 (HealthDay News) -- Testing for variations of a gene that helps control blood clotting could one day help doctors write better prescriptions for warfarin, a clot-preventing drug that is taken by millions of Americans and is difficult to manage, researchers report.

The gene, designated VKORC1, was described only last year by a group led by Dr. Darrel W. Stafford at the University of North Carolina. Now researchers at the University of Washington in Seattle and Washington University in St. Louis say their study indicates that the version of the gene that an individual carries has a strong effect on warfarin activity.

"There are two different versions of the gene, high-dose and low-dose," explained Mark J. Rieder, research assistant professor in genome sciences at the University of Washington, and lead author of the report in the June 2 issue of the New England Journal of Medicine.

"There is a very strong effect, one of the predominant factors in describing variations in dosage effects," he added.

More than 23 million prescriptions for warfarin (Coumadin) were written in the United States in 2003, the researchers noted. It is widely used to help control a form of abnormal heartbeat called atrial fibrillation and is prescribed for a number of other reasons -- for example, to prevent dangerous clots that could endanger individuals with artificial heart valves.

The new study included 185 patients taking warfarin, most often for atrial fibrillation, at the University of Washington and at Washington University, Rieder said.

"We sequenced the gene in every patient and looked for genetic differences," he said. "When we found such genetic differences, we found an association with the warfarin dose an individual was taking."

One strong ethnic effect was found in Asians, he said. About 90 percent of the Asian patients had the low-dose version of the gene, Rieder said. "And that is what gives rise to the observation by clinicians that they require a lower dose on average."

Genetic variation is only partially responsible for differing responses to warfarin, Rieder said. A number of other factors, some as basic as age and weight, play a role. But genetic variation does explain about 25 percent of the variance in dose, which means that "this test describes almost as much of the variability that you can get from looking at all these other factors," Rieder said.

Genetic testing of VKORC1 could someday enter medical practice, Rieder said, helping doctors establish the proper dose of warfarin for each patient quicker and with fewer complications than now may occur.

"Eventually, patients will benefit from this," he said. "But a whole series of studies need to be done before you can carry it into the clinic."

Many doctors have developed expertise in managing the medication, Rieder noted. "They have been prescribing warfarin for a long time, and they are pretty good at it.'

Howard J. McLeod, a professor of medicine at Washington University who participated in the study, said that "using genetics could be a better approach than using clinical judgment alone. If genetics can add value to those specialists, it will add value to the standard of care."

More information

For more on warfarin, visit the National Library of Medicine.

SOURCES: Mark J. Rieder, Ph.D, research assistant professor in genomic sciences, University of Washington, Seattle; Howard J. McLeod, Pharm.D, professsor of medicine, Washington University, St. Louis; June 2, 2005, New England Journal of Medicine

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