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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
Linköping University, Department of Physics, Chemistry and Biology, Computational Biology . Linköping University, The Institute of Technology.
The Computational Medicine Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden/Clinical Gene Networks AB, Karolinska Science Park, Stockholm, Sweden.
Linköping University, Department of Physics, Chemistry and Biology, Computational Biology . Linköping University, The Institute of Technology.
The Computational Medicine Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden/Clinical Gene Networks AB, Karolinska Science Park, Stockholm, Sweden.
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2009 (English)In: PLoS Genetics, ISSN 1553-7390, Vol. 5, no 12, e1000754- p.Article in journal (Refereed) Published
Abstract [en]

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<10-27and-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, cellular and lesion expression of LDB2, and 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.

Place, publisher, year, edition, pages
PLoS Genetics , 2009. Vol. 5, no 12, e1000754- p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-52084DOI: 10.1371/journal.pgen.1000754OAI: oai:DiVA.org:liu-52084DiVA: diva2:279388
Note
On the day of the defence day the status of this article was: In Press.Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved
In thesis
1. Gene Expression Profiling of Human Atherosclerosis
Open this publication in new window or tab >>Gene Expression Profiling of Human Atherosclerosis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis is a progressive inflammatory disease that causes lipid accumulation in the arterial wall, leading to the formation of plaques. The clinical manifestations of plaque rupture—stroke and myocardial infarction—are increasing worldwide and pose an enormous economic burden for society. Atherosclerosis development reflects a complex interaction between environmental exposures and genetic predisposition. To understand this complexity, we hypothesized that a top-down approach—one in which all molecular activities that drive atherosclerosis are examined simultaneously—is necessary to highlight those that are clinically relevant. To this end, we performed whole-genome expression profiling in multiple tissues isolated from patients with coronary artery disease (CAD).

In the Stockholm Atherosclerosis Gene Expression (STAGE) study, biopsies of five tissues (arterial wall with and without atherosclerotic lesions, liver, skeletal muscle and visceral fat) were isolated from 124 CAD patients undergoing coronary artery bypass grafting surgery (CABG) at the Karolinska University Hospital, Solna and carotid lesions from 39 patients undergoing carotid artery surgery at Stockholm Söder Hospital. Detailed clinical characteristics of these patients were assembled together with a total of 303 global gene expression profiles obtained with the Affymetrix GeneChip platform.

In paper 1, a two-way clustering analysis of the data identified 60 tissue clusters of functionally related genes. One cluster, partly present in both visceral fat and atherosclerotic lesions, related to atherosclerosis severity as judged by coronary angiograms. Many of the genes in that cluster were also present in a carotid lesion cluster relating to intima-media thickness (IMT) in the carotid patients. The union of all three clusters relating to extent of atherosclerosis—referred to as the “A-module”—was overrepresented with genes belonging to the transendothelial migration of leukocyte (TEML) pathway. The transcription co-factor, Lim domain binding 2 (LDB2), was identified as putative regulator of the A-module and TEML pathway in validation studies including Ldb2-/- mice.

In paper 2, we investigated the increased incidence of postoperative complications in CABG patients with diabetes. Using the STAGE compendium, we identified an anti-inflammatory marker, dual-specificity phosphatase 1 (DUSP1), as a novel preoperative blood marker of risk for a prolonged hospital stay after CABG.

In paper 3, plaque age was determined with C14-dating in the carotid patients. Interestingly, the strongest correlation with plaque age was not the age of the patients or IMT. Rather, the strongest correlations were with plasma insulin levels and inflammatory gene expression.

Taken together, the findings in this thesis show that a top-down approach using multi-tissue gene expression profiling in CAD and C14-dating of plaques can contribute to a better understanding of the molecular processes underlying atherosclerosis development and to the identification of clinically useful biomarkers.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 43 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1282
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-52085 (URN)978-91-7393-502-9 (ISBN)
Public defence
2009-12-18, Thoraxaulan, Karolinska Universitetssjukhuset, Solna, N2:U1, Stockholm, 09:00 (English)
Opponent
Supervisors
Available from: 2009-12-03 Created: 2009-12-03 Last updated: 2009-12-07Bibliographically approved

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Hägg, SaraLundström, JesperNilsson, RolandBrinne, BjörnBradshaw, MariaTegnér, Jesper

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