Identification of unique venous thromboembolism-susceptibility variants in African-Americans.

Heit JA, Armasu SM, McCauley BM, Kullo IJ, Sicotte H, Pathak J, Chute CG, Gottesman O, Bottinger EP, Denny JC, Roden DM, Li R, Ritchie MD, de Andrade M
Thromb Haemost. 2017 117 (4): 758-768

PMID: 28203683 · PMCID: PMC5831339 · DOI:10.1160/TH16-08-0652

To identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.

MeSH Terms (21)

Adult African Americans Aged Biological Specimen Banks Case-Control Studies Databases, Genetic Electronic Health Records Female Genetic Association Studies Genetic Predisposition to Disease Humans Logistic Models Male Middle Aged Odds Ratio Phenotype Polymorphism, Single Nucleotide Risk Factors Sex Factors United States Venous Thromboembolism

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