title: Multi-organ expression profiling uncovers a gene module in coronary artery disease involving transendothelial migration of leukocytes and LIM domain binding 2: the Stockholm Atherosclerosis Gene Expression (STAGE) study.
abstract: Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10(-27 and-30)). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.
authors.affiliation: The Computational Medicine Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
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authors.lastname: Hägg
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
authors.forename: Jesper
authors.initials: J
authors.lastname: Lundström
authors.forename: Peri
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authors.lastname: Noori
authors.forename: Roland
authors.initials: R
authors.lastname: Nilsson
authors.forename: Hua
authors.initials: H
authors.lastname: Zhong
authors.forename: Shohreh
authors.initials: S
authors.lastname: Maleki
authors.forename: Ming-Mei
authors.initials: MM
authors.lastname: Shang
authors.forename: Björn
authors.initials: B
authors.lastname: Brinne
authors.forename: Maria
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authors.lastname: Bradshaw
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Bajic
authors.forename: Ann
authors.initials: A
authors.lastname: Samnegård
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.forename: Lee M
authors.initials: LM
authors.lastname: Kaplan
authors.forename: Bruna
authors.initials: B
authors.lastname: Gigante
authors.forename: Karin
authors.initials: K
authors.lastname: Leander
authors.forename: Ulf
authors.initials: U
authors.lastname: de Faire
authors.forename: Stefan
authors.initials: S
authors.lastname: Rosfors
authors.forename: Ulf
authors.initials: U
authors.lastname: Lockowandt
authors.forename: Jan
authors.initials: J
authors.lastname: Liska
authors.forename: Peter
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authors.lastname: Konrad
authors.forename: Rabbe
authors.initials: R
authors.lastname: Takolander
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Ivert
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.forename: Johan
authors.initials: J
authors.lastname: Björkegren
mesh_terms: D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D002339:Carotid Arteries / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D019295:Computational Biology; D003324:Coronary Artery Disease / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D060588:LIM Domain Proteins; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000235:genetics; D015203:Reproducibility of Results; D013548:Sweden; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C484572:LDB2 protein, human; D060588:LIM Domain Proteins; C106649:Ldb2 protein, mouse; D014157:Transcription Factors