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The Stockholm Atherosclerosis Gene Expression (STAGE) study: Global Gene Expression data from coronary and carotid artery disease patients

ABSTRACT: Tissue samples have been isolated during corornary artery by-pass grafting (CABG)surgery from the atheroscelrotic arterial wall (AAW, aortic root puncture for proxmal ligation of by-pass vessel), non-atherosclertoci arterial wall (NAAW, distal part of mammary artery used a graft for LAD), liver, skeletal muscle (Recturs m), pericardial mediastinal visceral fat) in CAD patients. Carotid lesions samples from 25 validation patients. We used microarrays to measure global gene expression in these tissues to cluster groups of functionally associated genes and then, second step clustering of patients within each cluster to link clusters to patient phenotypes primarily coronary stenosis (CAD) and Intima media thickness (IMT) in carotid stenosis patients. . All samples were taken during surgery. The time of operation was less than 3 hours in most instances. Sammon plots show strong clustering of tissue-specific arrays. Even separating AAW from NAAW and carotid lesions.

ORGANISM(S): Homo sapiens

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PROVIDER: S-DIXA-D-1134 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description: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.

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The Stockholm Atherosclerosis Gene Expression (STAGE) study: Global Gene Expression data from coronary and carotid artery disease patients

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