Researchers identify genetic variation to predict initial response to warfarin

Scientists have identified which variations of a specific gene determine a patient’s initial response to treatment with the blood-thinning (anticoagulant) drug warfarin. Researchers with the National Institutes of Health (NIH) Pharmacogenetics Research Network found that the gene VKORC1 plays a major role in determining a patient's initial sensitivity to warfarin treatment – when dosage amounts are most critical to prevent clotting problems in patients.

The study was conducted by researchers at Vanderbilt University and funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of General Medical Sciences (NIGMS), both part of NIH. The article, “Genetic Determinants of Initial Warfarin Response,” is published in the March 6, 2008, issue of the New England Journal of Medicine. An accompanying editorial written by NHLBI Director Elizabeth G. Nabel, M.D., and NHLBI Deputy Director Susan B. Shurin, M.D., on the role of pharmacogenomics is also in this week’s NEJM.

Researchers assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3) and VKORC1 haplotypes (designated A and nonA) in 297 patients starting warfarin therapy. They compared the participants' clinical characteristics and response to therapy, determined by international normalized ratio (INR) and bleeding events. Their findings confirm earlier research that the two genes, VKORC1 and CYP2C9, help predict how well a patient responds to warfarin. The new results take scientists’ understanding a step further and indicate that although both genes significantly influence response to the drug after the first two weeks of therapy, only variations of VKORC1 predict response within the first week of therapy.

The blood clotting variations in VKORC1 help explain why certain patients require a lower or higher dose of warfarin to get its full benefits. The findings could ultimately help doctors determine a patient’s optimal warfarin dose more quickly and precisely through genetic screening for the VKORC1 gene and could result in better warfarin dosing, thereby increasing the safety and effectiveness of treatment.

After the discovery of the two genes that play a role in warfarin responsiveness, the Food and Drug Administration (FDA) approved labeling changes in August 2007 instructing physicians to use genetic testing when determining initial dosage estimates for their patients. However, until now, information on genetic interactions with initial response to therapy was limited. An estimated 2 million people in the United States take the anticoagulant drug warfarin to prevent harmful clotting after a heart attack, stroke, or major surgery. Despite its wide use, physicians find the drug challenging to prescribe because individuals’ responses vary widely, and too high of a dose can result in excessive bleeding while too low a dose could allow dangerous blood clots to form.

Resources:

• Pharmacogenetics Research Network, www.nigms.nih.gov/initiatives/PGRN/

• Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), an integrated knowledge base for pharmacogenetics linking phenotypes and genotypes, supported by the NIH/NIGMS Pharmacogenetics Research Network and Database: http://www.pharmgkb.org/.

• "FDA Approves Updated Warfarin (Coumadin) Prescribing Information -- New Genetic Information May Help Providers Improve Initial Dosing Estimates of the Anticoagulant for Individual Patients," News release, Food and Drug Administration, August 16, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html

• "Genetic Variation Alters Response to Common Anti-Clotting Drug," News release, National Institute of General Medical Sciences, June 2, 2005. http://www.nigms.nih.gov/news/results/060205.html.

• WarfarinDosing.org, a free Web tool for health care professionals to estimate the beginning dose for patients who are starting warfarin therapy. Supported in part by NHLBI and the Barnes-Jewish Hospital Foundation.

Part of the National Institutes of Health (NIH), the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

NIGMS (http://www.nigms.nih.gov) supports basic biomedical research that is the foundation for advances in disease diagnosis, treatment, and prevention.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.