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Blood. 2016 Apr 14;127(15):1923-9. doi: 10.1182/blood-2015-09-668525. Epub 2016 Feb 17.

Novel genetic predictors of venous thromboembolism risk in African Americans.

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Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL;
Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN; Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Department of Pharmacology and Physiology and.
Department of Medicine, George Washington University, Washington, DC; Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA;
Veterans Affairs Medical Center, Washington, DC;
Department of Medicine, George Washington University, Washington, DC;
Division of Urology, Department of Surgery, University of Arizona College of Medicine, Tucson, AZ; and.
Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL.


Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 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 messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P< 6 × 10(-7)). These risk variants were found in higher frequency among populations of African descent (>20%) compared with 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 with controls (P= 9.87 × 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 that increase the risk of VTE in AAs, a population disproportionately affected by this disease.

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