UW News

June 2, 2005

UW researchers identify major genetic factor responsible for patient variability in warfarin response

UW Health Sciences/UW Medicine

University of Washington researchers have discovered that genetic variations may influence how individuals respond to a common coumarin-based anticoagulant called warfarin, according to an article published in the June 2 edition of the New England Journal of Medicine.

Research by Dr. Allan E. Rettie, professor and chair of medicinal chemistry in the University of Washington School of Pharmacy, Dr. Mark Rieder, research assistant professor in genome sciences, and their colleagues shows that warfarin response is highly dependent on the gene encoding vitamin K epoxide reductase complex 1 (VKORC1).

Millions of people use warfarin to prevent blood clotting after a heart attack, stroke or major surgery. However, the oral anticoagulant dose has to be carefully titrated, as too much of the drug can cause excessive bleeding and too little results in no therapeutic benefit. A retrospective study of the medical records of patients on long-term warfarin therapy showed that VKORC1 haplotypes can be used to stratify patients into low, intermediate and high-dose warfarin groups, and may explain differences in dose requirements among patients of different ancestries.

The research helps set the stage for the development of what is often called personalized or designer drug therapy, in which a person’s genetic makeup is used to individualize and optimize drug therapy.

“Used in conjunction with the clinical data that physicians routinely gather, this information should help guide selection of the correct dose for patients because VKORC1 alone accounts for a large portion of the dose variability,” said Rettie.

Rieder added, “Genetic variations in VKORC1 turn the gene up or down, which affects the amount of warfarin required to provide the desired anticoagulant response.”

The study means that physicians have another tool to help better dose patients in need of anticoagulants. Typically, a patient needs numerous clinic visits before a stabilizing dose of the drug is achieved.

“We think this gene test could help them get to the appropriate dose more quickly,” Rettie said. “However, prospective clinical studies on this are needed, now that the dominant genetic mechanisms that cause this variability have been established.”