Genes determine response to blood-clotting drug

The dose of the anti-blood clotting drug warfarin required by a patient is partly down to their genetic make-up, US researchers say. A team of scientists based at the University of Washington have shown that variations in a gene known as VKORC1 affect a person's response to warfarin. The scientists say their results, recently published in the New England Journal of Medicine, could prove to be a 'central factor' in setting the initial dose of the medicine in patients.

Millions of people take warfarin to prevent harmful blood clots after a heart attack, stroke or major surgery. But the proper dose can vary greatly between individuals, in a way that is difficult to predict. 'A small change in dose can have quite a large effect on blood processes', explained lead author Allan Rettie, adding 'too high of a dose can result in excessive bleeding, while too little of a dose could allow dangerous blood clots to form'. Currently, doctors use information such as a patient's sex, age, weight and medical history to set the dose, a process that can take months to get exactly right.

Previous research revealed that differences in a gene called CYP2C9 - which makes a protein that breaks down warfarin and other drugs in the body - account for about ten per cent of the variation in people's response to the blood-clotting medicine. In the latest study, the scientists focused on the VKORC1 gene, which makes a protein that helps control clotting. They identified variations that affected the gene's activity - how much protein it made. Depending on which version they had, patients fell into one of three groups: those who required low, high or intermediate doses. 'We found that 25 per cent of the variance in warfarin dose is due to this one gene', said Rettie, adding 'this is probably the single biggest contributor to variability in people's response to the drug'.

The findings represent another advance in the field of pharmacogenetics - the study of how genetic variations can alter people's responses to medicines. 'It shows one important way in which we are beginning to apply knowledge about the human genome for treating disease and improving human health', said Elias Zerhouni, director of the US National Institutes of Health. Rettie and co-author Mark Rieder say that while genetic screening for the VKORC1 gene could result in better warfarin dosing, more research is required to find out if 'knowledge of genetic variability truly improves patient treatment' with the drug.