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

Abstract

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.

Keywords: African Americans; Genetic variation; association analyses; venous thromboembolism.

Conflict of interest statement

Conflicts of interest

None declared.

Figures

Figure 1. Manhattan plot of GWA of VTE among African-Americans using 1000G

Imputed data adjusted for site-platform, age, sex, stroke, PC1, PC2 and the sickle cell anaemia risk variant, keeping only high quality imputed SNPs (0.8 0.01.

Figure 2

Q-Q plot of the p-values of the GWA of VTE among African-Americans results from Figure 1, including the inflation factor of 1.0053 and SE of 1.7388E-06.

Figure 3

Boxplots of the gene expression probes in LEMD3 (A, B), LOC100130298 (C, D), and LY86 (E) genes.