A new understanding of the genetics underlying response to warfarin may guide development of genetic testing that will allow doctors to personalize dose for best response and minimal risk of complications, according to an article in the March 6 issue of the New England Journal of Medicine.

Prior to the current work, scientists knew that two genes influence response to warfarin: CYP2CP codes for an enzyme that degrades warfarin. The other, VKORC1, encodes the enzyme that warfarin blocks in exerting its effects. What was not known was the relative impact of genotype when warfarin is first given.

In 297 patients starting warfarin therapy, researchers determined CYP2C9 genotypes (CYP2C9 *1, *2, and *3) and VKORC1 haplotypes (designated A and non-A). Clinical data included response to therapy as determined by the international normalized ratio INR and bleeding events.

Study outcomes were the time to first INR within the therapeutic range, time to the first INR of more than 4, time above the therapeutic INR range, INR response over time, and the warfarin dose requirement.

Patients with the A/A haplotype of VKORC1 had a significantly decreased time to first INR within the therapeutic range and to the first INR of more than 4. In contrast, the CYP2C9 genotype was not a significant predictor of the time to first INR within the therapeutic range, but was a significant predictor of the time to first INR of more than 4. Both CYP2C9 genotype and VKORC1 haplotype had a significant influence on required warfarin dose after the first two weeks of therapy.

"Our study showed that during the first weeks of warfarin therapy, variation in the VKORC1 gene is a more important contributor to sensitivity to warfarin than variation in the CYP2C9 gene," said the study's senior author, C. Michael Stein, MB, ChB, associate chief of Clinical Pharmacology.

The findings exemplify the potential value of pharmacogenomics, the study of how genetic variation affects individual responses to medication, said Dan Roden, MD, vice chancellor for Personalized Medicine, who contributed to the study.

Last year the U.S. Food and Drug Administration (FDA) updated labeling for warfarin to notify doctors that genetic testing could help improve estimates for initial dosages.

"This is the fifth or sixth example of a drug that has had its label changed in the last two years based on the notion that there are genetic determinants of response," Roden said. "Warfarin is probably the first example of a widely used drug where we're predicting variability in a large chunk of the population, and the variability may make a difference in outcome."