Novel genetic predictors of venous thromboembolism risk in African Americans

Wenndy Hernandez, Eric R. Gamazon, Erin Smithberger, Travis J. O'Brien, Arthur F. Harralson, Matthew Tuck, April Barbour, Rick A. Kittles, Larisa H. Cavallari and Minoli A. Perera

Key points

  • Our study has identified common genetic risk factors for VTE among AAs.

  • These risk factors are associated with decreased thrombomodulin gene expression, suggesting a mechanistic link.


Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the U.S. with African Americans (AAs) having a 30 - 60% higher incidence compared to other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study (GWAS) in AAs comprised of 578 subjects followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the mRNA expression differences in VTE cases and controls. We identified and replicated SNPs on chromosome 20 (rs2144940, rs2567617, and rs1998081) which increased risk of VTE by 2.3 fold (p < 6 x 10-7). These risk variants were found in higher frequency among populations of African descend (>20%) compared to other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD) and the expression of THBD is lower among VTE cases compared to controls (p = 9.87 x 10-6). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants which increase the risk of VTE in AAs; a population disproportionately affected by this disease.

  • Submitted September 10, 2015.
  • Accepted January 7, 2016.