Genetic variations that alter response to warfarin identified

Issue: July 2013

Researchers have identified a common genetic variation that can influence the therapeutic dose of warfarin in African Americans. The discovery, reported online in The Lancet, demonstrates that those of African ancestry who carry the rs12777823 variant may require a lower dose of warfarin as compared with those who do not carry the single nucleotide polymorphism, according to a press release.

“Adding this genetic marker — found in more than 40% of African-American patients in the study — to standard dosing algorithms improved the predictability of warfarin dosing by 21% in these individuals, which has the potential to increase the safety and effectiveness of this notoriously hard to dose drug,” researcher Julie A. Johnson, PharmD, distinguished professor of pharmacy and medicine and director of the Center for Pharmacogenomics at University of Florida, Gainesville, stated in the release.

Julie A. Johnson

Earlier research demonstrated that two genes, VKORC1 and CYP2C9, can explain about one-third of the difference in warfarin response in people of Asian and European ancestry. However, these genetic markers appear less predictive of dosing regimens in African Americans, according to information in the release.

Minoli A. Perera, PharmD, of the section of genetic medicine at University of Chicago, and colleagues conducted a genome-wide association study to identify additional genetic factors and control warfarin dose requirements in African Americans. The researchers analyzed health information and DNA samples from African-American adults on stable doses of warfarin. Analysis focused on a discovery cohort of 533 participants and a replication cohort of 432 participants. All were from the International Warfarin Pharmacogenomics Consortium (IWPC) sites and the University of Alabama at Birmingham.

Genetic determinant of variability

Genome-wide analysis revealed that the strongest signals were clustered around VKORC1. A strong association between the rs12777823 variant in the CYP2C cluster on chromosome 10 and warfarin dose also emerged. This finding was corroborated in the replication cohort.

The data further suggest that African-American carriers of one or two copies of this polymorphism may need a warfarin dose reduction of 7 mg to 9 mg less per week compared with noncarriers. Individuals heterozygous for the rs12777823 allele need a dose reduction of 6.92 mg per week and individuals homozygous for the allele need a reduction of 9.34 mg per week, according to the study abstract.

“A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. … Our findings suggest that warfarin dose variability is affected by variants other than the well-established VKORC1 and CYP2C9 ones in African Americans; these new variants could improve dose prediction in these individuals,” the researchers wrote.

Practical use of genetic testing

In a simultaneously published comment, Mark J. Alberts, MD, of the University of Texas Southwestern Medical Center, said the use of genetic testing has been advocated by the FDA to help guide warfarin dosing.

“However, the practical aspects (and limitations) have not been fully appreciated,” Alberts wrote. “Genetic testing has several challenges; it is not widely available in some areas; it is costly; and clinicians often can identify the correct dose before test results are available. If these problems were corrected, the actual dose of such tests might increase substantially.”

For more information:

Alberts MJ. Lancet. 2013;doi:10.1016/S0140-6736(13)60942-3.

Perera MA. Lancet. 2013;doi:10.1016/S0140-6736(13)60681-9.

Disclosure: The study was funded by the NIH, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research and the Wellcome Trust. Alberts reports serving as a consultant and speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck and Pfizer.