TY - JOUR
T1 - Novel genetic predictors of venous thromboembolism risk in African Americans
AU - Hernandez, Wenndy
AU - Gamazon, Eric R.
AU - Smithberger, Erin
AU - O'Brien, Travis J.
AU - Harralson, Arthur F.
AU - Tuck, Matthew
AU - Barbour, April
AU - Kittles, Rick A.
AU - Cavallari, Larisa H.
AU - Perera, Minoli A.
N1 - Funding Information:
The authors thank Dan Nicolae, Department of Medicine, Section of Genetic Medicine, for his valuable input in the analysis process; and the RIKEN research institute for their ongoing collaboration that provided our high-quality genome-wide genotyping. This study was supported (in part) by research funding from the National Collaborative on Aging Faculty Awards Program (T.J.O., A.F.H., and M.T.); the American Heart Association Midwest Affiliate Grant-In-Aid (10GRNT3750024) (L.H.C.); the National Institutes of Health National Heart, Lung, and Blood Institute grants K23 HL089808-01A2 and R21 HL106097-01A1 and National Institute on Minority Health and Health Disparities grant 1R01MD009217-01 (M.A.P.); the University of Chicago Cardiovascular Sciences Training grant 5T32 HL007381 (W.H.); CA157823, and National Institutes of Health National Institute of Mental Health grants R01 MH101820 and R01 MH090937 (E.R.G.).
Publisher Copyright:
© 2016, American Society of Hematology. All rights reserved.
PY - 2016/4/14
Y1 - 2016/4/14
N2 - 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 riskof 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.
AB - 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 riskof 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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U2 - 10.1182/blood-2015-09-668525
DO - 10.1182/blood-2015-09-668525
M3 - Article
C2 - 26888256
AN - SCOPUS:84963749624
SN - 0006-4971
VL - 127
SP - 1923
EP - 1929
JO - Blood
JF - Blood
IS - 15
ER -