Genetic variation alters response to anti-clotting drug warfarin

Millions of people take the anticoagulant drug warfarin 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, according to a new study published in the June 2 issue of The New England Journal of Medicine.

By looking at the genetic makeup of people on warfarin, researchers at the University of Washington in Seattle and Washington University in St. Louis learned 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. This line of work ultimately could help doctors determine each patient's warfarin dose more quickly and precisely.

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, M.D. "It shows one important way in which we are beginning to apply knowledge about the human genome for treating disease and improving human health."

Warfarin (trade names include CoumadinTM) is the most commonly prescribed oral anti-clotting drug. Allan E. Rettie, Ph.D., University of Washington professor of medicinal chemistry and senior author of the paper, estimated that 2 million people in the United States take warfarin on any given day.

Despite its wide use, physicians find the drug challenging to prescribe.

"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 can result in excessive bleeding while too little of a dose could allow dangerous blood clots to form.

Doctors 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, Ph.D., an assistant professor in 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.

The team focused on another gene: vitamin K epoxide reductase (VKORC1), which makes a protein that helps control clotting and is the key target of warfarin. The researchers analyzed the VKORC1 gene's DNA sequence in 186 patients 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.

"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, the researchers said, 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 [overall] 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.

Although Rettie and Rieder said there's a high probability that genetic screening for the VKORC1 gene could result in better warfarin dosing, they agreed that more studies need to be done first.

"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."