title: 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.
authors.affiliation: John A. Heit, MD, Stabile 6-Hematology Research, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA, Tel.: +1 507 284 4634, Fax: +1 507 266 9302, E-mail: heit.john@mayo.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Heit
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.forename: Bryan M
authors.initials: BM
authors.lastname: McCauley
authors.forename: Iftikhar J
authors.initials: IJ
authors.lastname: Kullo
authors.forename: Hugues
authors.initials: H
authors.lastname: Sicotte
authors.forename: Jyotishman
authors.initials: J
authors.lastname: Pathak
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Chute
authors.forename: Omri
authors.initials: O
authors.lastname: Gottesman
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Bottinger
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D018070:Biological Specimen Banks; D016022:Case-Control Studies; D030541:Databases, Genetic; D057286:Electronic Health Records; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D014481:United States / Q000453:epidemiology; D054556:Venous Thromboembolism / Q000175:diagnosis / Q000208:ethnology* / Q000235:genetics*
keywords: African Americans; Genetic variation; association analyses; venous thromboembolism