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Warfarin Bleeding Risk SNPs Identified in African Americans

NEW YORK (GenomeWeb) – A Northwestern University-led team has identified a handful of new variants that appear to predispose individuals of African descent to increased risk of bleeding when taking the anticoagulant warfarin.

As they reported online today in the Journal of the American Medical Association, the researchers began with a case-control genome-wide association study involving 31 individuals who experienced warfarin-related bleeding and 184 control individuals who were treated with warfarin but did experience subsequent bleeding problems, genotyped at almost 8.2 million SNPs using the Illumina 610 Quad BeadChip at RIKEN's Center for Genomic Medicine.

In the process, the team found four suspicious SNPs in linkage disequilibrium on chromosome 6. Following a replication analysis in another 40 cases and 148 bleeding-free, warfarin-treated controls, one of the variants — rs78132896 in the promoter of the EPHA7 protein tyrosine kinase ephrin subfamily gene — showed genome-wide significant ties to bleeding risk in the African Americans assessed, based on a coagulation assay known as the international normalized ratio (INR).

"In this preliminary study involving patients of African descent taking warfarin, [four] single nucleotide polymorphisms in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding at an INR of less than four," corresponding author Minoli Perera, a pharmacology researcher at Northwestern, and colleagues wrote, though they cautioned that "[v]alidation of these findings in an independent prospective cohort is required."

The team's subsequent in vitro expression assays indicated that rs78132896 SNP, in the EPHA7 promoter, and a variant in linkage disequilibrium in the gene's enhancer, appeared to correspond to more pronounced EPHA7 expression.

When they incorporated the rs78132896 SNP into an existing framework known as HAS-BLED, for predicting warfarin bleeding risk based on factors such as hypertension, liver function, age, and other factors, the researchers found that that variant seemed to slightly boost the classification accuracy of that approach.

They noted that the current analysis may ultimately help to predict and prevent bleeding in warfarin-treated individuals with African-American ancestry, who appear to experience higher rates of stroke, thromboembolic disease, and warfarin treatment-related major bleeding events.

"Although single nucleotide polymorphisms associated with bleeding have been identified in populations of European ancestry, the genetic basis for hemorrhagic complications in patients of African descent has not been well studied," the authors wrote. "Identifying these variants may help physicians make safer choices in anticoagulation therapy for this understudied patient population."