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
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ArticleAuthors
Hägg, SaraSkogsberg, Josefin
Lundström, Jesper
Noori, Peri
Nilsson, Roland
Zhong, Hua
Maleki, Shohreh
Shang, Ming-Mei
Brinne, Björn
Bradshaw, Maria
Bajic, Vladimir B.
Samnegård, Ann
Silveira, Angela
Kaplan, Lee M.
Gigante, Bruna
Leander, Karin
de Faire, Ulf
Rosfors, Stefan
Lockowandt, Ulf
Liska, Jan
Konrad, Peter
Takolander, Rabbe
Franco-Cereceda, Anders
Schadt, Eric E.
Ivert, Torbjörn
Hamsten, Anders
Tegnér, Jesper
Björkegren, Johan
KAUST Department
Computational Bioscience Research Center (CBRC)Date
2009-12-04Metadata
Show full item recordAbstract
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 Amodule 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. 2009 Hgg et al.Citation
Hägg S, Skogsberg J, Lundström J, Noori P, Nilsson R, et al. (2009) 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. PLoS Genet 5: e1000754. doi:10.1371/journal.pgen.1000754.Publisher
Public Library of Science (PLoS)Journal
PLoS GeneticsISSN
15537390PubMed ID
19997623PubMed Central ID
PMC2780352Handle URI
http://hdl.handle.net/10754/325276Scopus Count
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