The anticoagulant drug Warfarin ( Coumadin ) is commonly prescribed to prevent harmful clotting after a heart attack, stroke, or major surgery. But the proper dose of Warfarin can vary greatly and can be hard to predict.
Some of this variability may boil down to a recently identified gene involved in blood clotting.

Researchers at the University of Washington in Seattle and Washington University in St. Louis found that variations in a gene involved in blood clotting may explain why certain people require a lower or higher dose of Warfarin to get its full benefits.
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The study, part of the NIH Pharmacogenetics Research Network, was supported by three components of the National Institutes of Health ( NIH ): the National Institute of General Medical Sciences ( NIGMS ); the National Heart, Lung, and Blood Institute ( NHLBI ); and the National Institute of Environmental Health Sciences ( NIEHS ).

“ This research points to the value of pharmacogenetics, the study of how genetic variations can alter people’s responses to medicines, ” said NIH Director Elias A. Zerhouni. “ It shows one important way in which we are beginning to apply knowledge about the human genome for treating disease and improving human health.”

“ There is a narrow window between too much and too little effect,” explained Rettie. “A small change in dose can have quite a large effect on blood processes.”
For example, too high of a dose of Warfarin can result in excessive bleeding while too little of a dose could allow dangerous blood clots to form.

Physicians primarily use information about a patient’s sex, age, weight, and medical history to set the initial Warfarin dose.
However, it can take several months of clinic visits and needle pricks to determine an individual’s ideal dose.
Scientists know that variations in a gene encoding the CYP2C9 enzyme that metabolizes Warfarin account for about 10 percent of the difference in people’s responses to the drug, but tests for these genetic variations are not routinely performed.

Rettie and his colleague Mark J. Rieder, of the University of Washington’s Department of Genome Sciences and first author of the paper, wanted to better understand the genetic basis for variability in Warfarin response. “ If you want to predict dose, you need to know more about the genes that control variability,” explained Rieder.

Researchers focused on another gene: vitamin K epoxide reductase ( VKORC1 ), which makes a protein that helps control clotting and is the key target of Warfarin. They analyzed the VKORC1 gene’s DNA sequence in 186 patients on a stabilized dose of Warfarin and searched for common DNA variations responsible for changing the gene’s activity and the amount of protein it made.

“ We did find genetic variations that appear to turn up the gene or turn it down,” said Rieder.

By matching the genetic variations to actual Warfarin doses, the scientists discovered that people with a particular variation of the VKORC1 gene generally took similar doses of Warfarin.

The genetic variations divided patients into three main groups: low, high, and intermediate dose.
The intermediate group included people with a combination of the low- and high-dose gene versions.
These results suggest that information about the VKORC1 gene could predict a person’s response to the anti-clotting drug.

“ We found that 25 percent of the variance in Warfarin dose is due to this one gene,” said Rettie.
“ 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.”

The team also learned that certain population groups tended to have a higher prevalence of a particular VKORC1 variation.
While Asian Americans generally had the low-dose variation, African Americans had the high-dose version. European Americans fell in the middle.

“ What we’ve done is the basic science,” said Rettie. “ This complete genetic analysis of VKORC1 provides the mechanistic framework and impetus for prospective studies in a clinical setting. Such studies could determine if knowledge of genetic variability truly improves patient treatment with this frontline anticoagulant drug.”

Source: The New England Journal of Medicine, 2005


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