Warfarin Bleeding Risk SNPs Identified in African Americans

Major Warfarin-related bleeding occurs more frequently in African Americans than in other populations. Identification of potential genetic factors related to this adverse event may help identify at-risk patients.

Warfarin is an anticoagulant used to prevent heart attacks, strokes, and blood clots. A handful of new variants have been identified that appear to predispose individuals of African descent to increased risk of bleeding when taking the anticoagulant warfarin.

Scientists at Northwestern University (Chicago, IL, USA) and their colleagues conducted a 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. The team genotyped at almost 8.2 million single nucleotide polymorphisms (SNPs) using the Illumina 610 Quad BeadChip. Major bleeding was defined as bleeding requiring hospitalization, causing a decrease in hemoglobin level of more than 2 g/dL, requiring blood transfusion, or any combination of the 3, while taking warfarin at an international normalized ratio INR of less than 4.

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). 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. The SNP rs78132896 occurred in 11 cases (35.5%) and nine controls (4.9%) in the discovery cohort, and the association was confirmed in the replication cohort, the SNP was present in 14 cases (35.0%) and seven controls (4.8%).

Minoli A. Perera, PharmD, PhD, an associate professor and a senior author of the study, said, “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.” The study was published on October 23, 2018, in the Journal of the American Medical Association.

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