"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"*, explains Julie Johnson from the University of Florida in the USA, who led the research.
Warfarin—used to prevent blood clots in patients with atrial fibrillation, a history of previous blood clots, and after major surgery—is one of the most widely prescribed drugs in the world, accounting for more than 35 million prescriptions in the USA in 2011 alone.
But dose requirements vary widely between people making it difficult to get the dose right, and warfarin contributes to a third of hospitalisations for adverse drug reactions in people older than 65 years in the USA.
Earlier studies have shown that two genes, VKORC1 and CYP2C9, can explain about 30% of the difference in warfarin response in people of European and Asian ancestry. However, these genetic markers are less predictive of dosing regimens in African Americans.
To identify additional genetic factors that control warfarin dose requirements in African Americans, Johnson and colleagues analysed health information and DNA samples from 533 African-American adults on stable doses of warfarin from the International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham.
The sweep of genomes found that the strongest signals were clustered around the well established VKORC1, but also identified a strong association between the rs12777823 variant on chromosome 10 and warfarin dose. This finding was corroborated in an independent cohort of 432 additional African-American patients.
The findings suggest that African Americans who carry one or two copies of this polymorphism need a dose reduction of roughly 7–9 mg less per week than other patients.
Commenting on the study, Mark Alberts from UTSW Medical Center in Texas, USA says, "Use of genetic backgrounds to help to guide warfarin dosing has been advocated for several years by the US Food and Drug Administration… However, the practical aspects (and limitations) have not been fully appreciated. 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 use of such tests might increase substantially."
NOTES TO EDITORS:
*Quote direct from author and cannot be found in text of Article.
Journal
The Lancet