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

John A. Heit, Sebastian M. Armasu, Bryan M. McCauley, Iftikhar Jan Kullo, Hugues Sicotte, Jyotishman Pathak, Christopher G. Chute, Omri Gottesman, Erwin P. Bottinger, Joshua C. Denny, Dan M. Roden, Rongling Li, Marylyn D. Ritchie, Mariza De Andrade

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 crossvalidation, 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-ß-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.

Original languageEnglish (US)
Pages (from-to)758-768
Number of pages11
JournalThrombosis and Haemostasis
Volume117
Issue number4
DOIs
StatePublished - 2017

Fingerprint

Venous Thromboembolism
African Americans
Single Nucleotide Polymorphism
Electronic Health Records
Gene Expression
Genome
Untranslated RNA
Genome-Wide Association Study
DNA
Genomics
Epigenomics
Lipopolysaccharides
Meta-Analysis
Down-Regulation
Logistic Models
Stroke
Genotype
Cell Proliferation
Phenotype
Genes

Keywords

  • African Americans
  • Association analyses
  • Genetic variation
  • Venous thromboembolism

ASJC Scopus subject areas

  • Hematology

Cite this

Identification of unique venous thromboembolism-susceptibility variants in African-Americans. / Heit, John A.; Armasu, Sebastian M.; McCauley, Bryan M.; Kullo, Iftikhar Jan; Sicotte, Hugues; Pathak, Jyotishman; Chute, Christopher G.; Gottesman, Omri; Bottinger, Erwin P.; Denny, Joshua C.; Roden, Dan M.; Li, Rongling; Ritchie, Marylyn D.; De Andrade, Mariza.

In: Thrombosis and Haemostasis, Vol. 117, No. 4, 2017, p. 758-768.

Research output: Contribution to journalArticle

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 2017, 'Identification of unique venous thromboembolism-susceptibility variants in African-Americans', Thrombosis and Haemostasis, vol. 117, no. 4, pp. 758-768. https://doi.org/10.1160/TH16-08-0652
Heit, John A. ; Armasu, Sebastian M. ; McCauley, Bryan M. ; Kullo, Iftikhar Jan ; Sicotte, Hugues ; Pathak, Jyotishman ; Chute, Christopher G. ; Gottesman, Omri ; Bottinger, Erwin P. ; Denny, Joshua C. ; Roden, Dan M. ; Li, Rongling ; Ritchie, Marylyn D. ; De Andrade, Mariza. / Identification of unique venous thromboembolism-susceptibility variants in African-Americans. In: Thrombosis and Haemostasis. 2017 ; Vol. 117, No. 4. pp. 758-768.
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AU - Sicotte, Hugues

AU - Pathak, Jyotishman

AU - Chute, Christopher G.

AU - Gottesman, Omri

AU - Bottinger, Erwin P.

AU - Denny, Joshua C.

AU - Roden, Dan M.

AU - Li, Rongling

AU - Ritchie, Marylyn D.

AU - De Andrade, Mariza

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