Association of Genetic Variants With Warfarin-Associated Bleeding Among Patients of African Descent
Authors: Tanima De, Cristina Alarcon, Wenndy Hernandez, Ina Liko, Larisa H. Cavallari, Julio D. Duarte, Minoli A. Perera
Journal: JAMA (2018)

<h3>Importance</h3> 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. <h3>Objective</h3> To identify genetic factors associated with warfarin-related bleeding in patients of African descent at an international normalized ratio (INR) of less than 4. <h3>Design, Setting, and Participants</h3> A case-control genome-wide association study involving patients of African descent taking warfarin was conducted in a discovery cohort (University of Chicago [2009-2011] and the University of Illinois at Chicago [2002-2011]), and associations were confirmed in a replication cohort (University of Chicago [2015-2016]). Potential population stratification was examined in the discovery cohort by principal component analysis. Odds ratios (ORs) and 95% CIs were computed for bleeding risk by logistic regression analysis. Summary statistics from the discovery and the replication cohorts were analyzed with a fixed effects meta-analysis. The potential influence of single-nucleotide polymorphisms (SNPs) on gene expression was studied by luciferase expression assays. <h3>Exposures</h3> Single-nucleotide polymorphisms associated with warfarin-related bleeding. <h3>Main Outcomes and Measures</h3> Major bleeding—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 INR of less than 4. <h3>Results</h3> The discovery cohort consisted of 31 cases (mean age, 60.1 years [SD, 14.9 years], 26 women [83.9%]) and 184 warfarin-treated controls (mean age, 57.1 years [SD, 15.7 years]) with no documented bleeding. The replication cohort consisted of 40 cases (mean age, 55.6 years [SD, 17.3 years], 27 women [67.5%]), and 148 warfarin-treated controls (mean age, 55.4 years [SD, 17.1 years]; 98 women [66.2%]) with no documented bleeding. In the discovery cohort, 4 SNPs in linkage disequilibrium on chromosome 6 (rs115112393,rs16871327,rs78132896, andrs114504854) were associated with warfarin-related bleeding but did not reach genome-wide significance. The SNPrs78132896occurred in 11 cases (35.5%) and 9 controls (4.9%) in the discovery cohort (OR, 8.31; 95% CI, 3.2-21.5;<i>P</i> &lt; 6.21 × 10<sup>−8</sup>), and the association was confirmed in the replication cohort (the SNP was present in 14 cases [35.0%] and 7 controls [4.8%]; OR, 8.24; 95% CI, 3.1-25.3,<i>P</i> = 5.64 × 10<sup>−5</sup>). Genome-wide significance of this SNP was achieved when the cohorts were combined via meta-analysis (OR, 8.27; 95% CI, 4.18-16.38;<i>P</i> = 2.05 × 10<sup>−11</sup>). These SNPs are found only in people of African descent. In vitro luciferase expression assays demonstrated thatrs16871327(enhancer SNP) andrs78132896(promoter SNP) risk alleles together increased<i>EPHA7</i>gene (Entrez Gene2045) transcription by a mean of 14.95 (SD, 1.7) compared with wild-type alleles (mean, 9.56 [SD, 0.84]; difference, 5.39; 95% CI, 4.1-6.6;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> In this preliminary study involving patients of African descent taking warfarin, 4 single-nucleotide polymorphisms in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding at INR of less than 4. Validation of these findings in an independent prospective cohort is required.