SEM of blood corpuscles in clot

Genetic variation alters response to warfarin

2/6/05. By NIH/National Institute of General Medical Sciences

Variation in a blood clotting gene may help predict the correct dose of the anticoagulant 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 dosage 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 2 June 2005 issue of the New England Journal of Medicine.

By looking at the genetic make-up 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 dosage of warfarin to get its full benefits. This line of work ultimately could help doctors to determine each patient's warfarin dosage more quickly and precisely.

Warfarin is the most commonly prescribed oral anticlotting drug. Allan Rettie, University of Washington professor of medicinal chemistry and senior author of the paper, estimated that 2 million people in the USA 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 a dosage can result in excessive bleeding while too low a dosage 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 dosage. However, it can take several months of clinic visits and needle pricks to determine an individual's ideal dosage. Scientists know that variations in a gene encoding the CYP2C9 enzyme (which metabolises warfarin) account for about 10 per cent of the difference in people's responses to the drug, but tests for these genetic variations are not performed routinely.

The researchers focused on gene called vitamin K epoxide reductase (VKORC1), which makes a protein that helps control clotting and is the key target of warfarin. The researchers analysed the VKORC1 gene's DNA sequence in 186 patients on a stabilised dosage of warfarin. They searched for common DNA variations responsible for changing the gene's activity and the amount of protein it made.

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 dosages of warfarin.

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

"We found that 25 per cent 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-dosage variation, African Americans had the high-dosage version. European Americans fell in the middle.

Although Rettie said that there was a high probability that genetic screening for the VKORC1 gene could result in better warfarin dosing, the researchers agreed that more studies needed to be done first. "What we've done is the basic science," he said. "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."

Adapted from a news release by the NIH/National Institute of General Medical Sciences .

Image credit: David Gregory and Debbie Marshall

Further reading

Rieder MJ et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285–93. Abstract

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