Warfarin tablets
Researchers say they have identified single-nucleotide polymorphisms (SNPs) that are associated with increased bleeding risk in African-American patients on warfarin.
A retrospective study revealed four SNPs associated with increased bleeding risk in African Americans with an international normalized ratio (INR) of less than 4.
One of these SNPs was seen in more than a third of bleeding cases and less than 5% of controls.
These preliminary findings could have implications for patients of African descent, but independent validation of the study results are needed, according to Minoli A. Perera, PharmD, PhD, of Northwestern University in Chicago, and her coauthors.
The researchers reported their findings in JAMA.
The report covered findings in a discovery cohort of African-American patients from a genome-wide study conducted at the University of Chicago and a replication cohort of patients who self-identified as African American and had routinely received care at University of Chicago hospitals.
The discovery cohort included 31 patients with major bleeding that occurred at an INR less than 4 and 184 controls with no documented history of bleeding related to warfarin.
In that cohort, Dr. Perera and her colleagues found four SNPs in linkage disequilibrium on chromosome 6 associated with warfarin-related bleeding:
- rs115112393
- rs16871327
- rs78132896
- rs114504854.
In particular, rs78132896 was found in 35.5% of cases (11/31) and 4.9% of controls (9/184), with an odds ratio of 8.31 (95% confidence interval [CI], 3.2-21.5).
The replication cohort, including 40 cases and 148 warfarin-treated controls, was genotyped specifically for rs78132896. The SNP was similarly found in 35.0% of cases (14/40) and 4.8% of controls (7/148), with an odds ratio of 8.24 (95% CI, 3.1-25.3).
“Genome-wide significance of this cohort was achieved when the cohorts were combined via meta-analysis,” the researchers wrote. They reported an odds ratio of 8.27 for that analysis (95% CI, 4.18-16.38).
Further analysis showed that, compared with wild-type alleles, the rs16871327 and rs78132896 risk alleles increased EPHA7 gene transcription.
Expression of the EPHA7 gene on vascular endothelial cells and peripheral lymphocytes is increased during inflammation, according to Dr. Perera and her coauthors. Increased EPHA7 expression might lead to bleeding in patients who are taking warfarin.
“This haplotype might also have potential implications for bleeding risk with direct oral anticoagulants,” the researchers wrote.
Dr. Perera and her coauthors reported no conflicts of interest related to their work on this study, which was funded by grants from the National Heart, Lung, and Blood Institute; the National Institute of General Medicine; the National Institutes of Health; and the American Heart Association Midwest Affiliate; as well as a research award from the University of Illinois at Chicago College of Pharmacy.