title: Identification of CAD candidate genes in GWAS loci and their expression in vascular cells.
abstract: Recent genome-wide association studies (GWAS) have identified 35 loci that significantly associate with coronary artery disease (CAD) susceptibility. The majority of the genes represented in these loci have not previously been studied in the context of atherosclerosis. To characterize the roles of these candidate genes in the vessel wall, we determined their expression levels in endothelial, smooth muscle, and macrophage cells isolated from healthy, prelesioned, and lesioned mouse aortas. We also performed expression quantitative locus (eQTL) mapping of these genes in human endothelial cells under control and proatherogenic conditions. Of the 57 genes studied, 31 were differentially expressed in one or more cell types in disease state in mice, and the expression levels of 8 were significantly associated with the CAD SNPs in human cells, 7 of which were also differentially expressed in mice. By integrating human and mouse results, we predict that PPAP2B, GALNT4, MAPKAPK5, TCTN1, SRR, SNF8, and ICAM1 play a causal role in the susceptibility to atherosclerosis through a role in the vasculature. Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilibrium blocks.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA, USA.
authors.forename: Ayca
authors.initials: A
authors.lastname: Erbilgin
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.forename: Casey E
authors.initials: CE
authors.lastname: Romanoski
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.forename: Raffi
authors.initials: R
authors.lastname: Hagopian
authors.forename: Judith A
authors.initials: JA
authors.lastname: Berliner
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics* / Q000473:pathology; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics; D010711:Phosphatidate Phosphatase / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D019998:Racemases and Epimerases / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D000097763:Polypeptide N-acetylgalactosaminyltransferase; D000099300:Serine Racemase
chemical_list: D001057:Apolipoproteins E; D056827:Endosomal Sorting Complexes Required for Transport; D018799:Intercellular Adhesion Molecule-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017350:N-Acetylgalactosaminyltransferases; D010711:Phosphatidate Phosphatase; D017346:Protein Serine-Threonine Kinases; D019998:Racemases and Epimerases; D011973:Receptors, LDL; D000097763:Polypeptide N-acetylgalactosaminyltransferase; D000099300:Serine Racemase; C573420:ICAM1 protein, human; C525859:SNF8 protein, human; C561486:Tctn1 protein, human; C111049:MAP-kinase-activated kinase 5; C521833:PLPP3 protein, human
keywords: atherosclerosis; coronary artery disease; endothelium; genetics; genome-wide association study; macrophages; smooth muscle cells