Log in to MyACC
Genetic Variants With Bleeding in African Americans on Warfarin
Study Questions:
What are genetic factors associated with warfarin-induced bleeding at an international normalized ratio (INR) of <4 in patients of African descent?
Methods:
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. The potential influence of single-nucleotide polymorphisms (SNPs) on gene expression was studied by luciferase expression assays. Major bleeding was defined as bleeding requiring hospitalization, causing a decrease in hemoglobin of >2 g/dl, requiring blood transfusion or any combination of the three.
Results:
The discovery cohort consisted of 31 cases and 184 warfarin-treated controls with no documented bleeding. The replication cohort consisted of 40 cases and 148 warfarin-treated controls with no documented bleeding. In the discovery cohort, four SNPs 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 nine controls (4.9%) in the discovery cohort (odds ratio [OR], 8.31; 95% confidence interval [CI], 3.2-21.5), and the association was confirmed in the replication cohort. 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). These SNPs are found only in people of African descent.
Conclusions:
In this preliminary study involving patients of African descent taking warfarin, four SNPs in linkage disequilibrium on chromosome 6 were associated with an increased risk of major bleeding at an INR of <4. Validation of these findings in an independent prospective cohort is required.
Perspective:
African Americans are at increased risk of warfarin-related bleeding. The study findings suggest there may be a population-specific genetic risk factor that exposes African Americans to increased risk of bleeding related to warfarin. The next step would be prospective validation to confirm the findings. If findings are validated, screening for polymorphisms would allow for tailoring therapies that are safer.
Clinical Topics: Anticoagulation Management, Prevention
Keywords: African Americans, Anticoagulants, Blood Transfusion, Chromosomes, Human, Pair 6, Genetic Variation, Genome-Wide Association Study, Hemoglobins, Hemorrhage, International Normalized Ratio, Polymorphism, Single Nucleotide, Primary Prevention, Risk Factors, Warfarin
< Back to Listings
