Genetic Variation Affects Clotting

A new study has found that variations in a gene involved in blood clotting may account for the difficulty doctors have in deciding on the proper dose of warfarin, a common anticoagulant.

Warfarin (trade names include Coumadin) is prescribed by doctors to prevent harmful blood clotting after a heart attack, stroke, or major surgery. However, the proper dose can vary a lot and be hard to predict. "There is a narrow window between too much and too little,” explained senior author Allan E. Rettie, Ph.D., professor of medicinal chemistry at the University of Washington (Seattle, USA; www.washington.edu).

Researchers looked at the genetic background of people taking warfarin and found that variations in the gene encoding the CY2C9 enzyme that metabolizes warfarin account for about 10% of the difference in people's response to the drug. Doctors do not routinely test for these variations. The researchers also 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 found that genetic variations did turn this gene up or down, so information about a patients' variations could predict their response to warfarin. In addition, the researchers found that certain population groups tend to have a higher prevalence of a particular variation. Asian Americans tend to have a low-dose version, African-Americans have a high-dose version, and European Americans are in the middle.

"If you want to predict doses, you need to know more about the genes that control variability,” observed first author Mark J. Rieder, Ph.D., an assistant professor in the department of genome sciences at the University of Washington. The study was published in the June 2, 2005, issue of The New England Journal of Medicine.