[Skip to Content]
[Skip to Content Landing]
Views 1,186
Citations 0
Preliminary Communication
October 23/30, 2018

Association of Genetic Variants With Warfarin-Associated Bleeding Among Patients of African Descent

Author Affiliations
  • 1Northwestern University, Department of Pharmacology, Chicago, Illinois
  • 2University of Chicago, Section of Genetic Medicine, Department of Medicine, Chicago, Illinois
  • 3University of Illinois College of Pharmacy, Department of Pharmacy Practice, Chicago
  • 4University of Florida, College of Pharmacy, Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, Gainesville
JAMA. 2018;320(16):1670-1677. doi:10.1001/jama.2018.14955
Key Points

Question  Are specific single-nucleotide polymorphisms (SNPs) associated with increased risk of warfarin-associated bleeding among patients of African descent?

Findings  In this case-control genome-wide association study involving patients of African descent taking warfarin with an international normalized ratio of less than 4, four SNPs in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding in a discovery cohort of 215 patients (odds ratio [OR], 8.3) and a replication cohort of 188 patients (OR, 8.2), and reached genome-wide significance when the cohorts were combined using meta-analysis (OR, 8.3).

Meaning  Four single-nucleotide polymorphisms in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding among patients of African descent taking warfarin; however, validation of these findings in an independent prospective cohort is required.

Abstract

Importance  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.

Objective  To identify genetic factors associated with warfarin-related bleeding in patients of African descent at an international normalized ratio (INR) of less than 4.

Design, Setting, and Participants  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.

Exposures  Single-nucleotide polymorphisms associated with warfarin-related bleeding.

Main Outcomes and Measures  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.

Results  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, and rs114504854) were associated with warfarin-related bleeding but did not reach genome-wide significance. The SNP rs78132896 occurred in 11 cases (35.5%) and 9 controls (4.9%) in the discovery cohort (OR, 8.31; 95% CI, 3.2-21.5; P < 6.21 × 10−8), 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, P = 5.64 × 10−5). 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; P = 2.05 × 10−11). These SNPs are found only in people of African descent. In vitro luciferase expression assays demonstrated that rs16871327 (enhancer SNP) and rs78132896 (promoter SNP) risk alleles together increased EPHA7 gene (Entrez Gene 2045) 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; P < .001).

Conclusions and Relevance  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.

×