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

• Published in: PLoS genetics 2009-12, Vol.5 (12), p.e1000754-e1000754
• Main Authors: Hägg, Sara, Skogsberg, 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
• Format: Article
• Language: English
• Subjects: Aged; Algorithms; Animals; Atherosclerosis; Atherosclerosis - genetics; Binding sites; Cardiovascular disease; Cardiovascular Disorders/Coronary Artery Disease; Carotid Arteries - pathology; Cell Movement - genetics; Chromosome mapping; Cluster Analysis; Cohort Studies; Computational Biology; Computational Biology/Molecular Genetics; Coronary Artery Disease - genetics; Coronary heart disease; Diagnosis; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks - genetics; Genetic aspects; Genetic Predisposition to Disease; Genetics and Genomics/Gene Expression; Genomes; Grants; Humans; Leukocytes - metabolism; Leukocytes - pathology; LIM Domain Proteins; Male; Medicin och hälsovetenskap; Messenger RNA; Mice; Migration; NATURAL SCIENCES; NATURVETENSKAP; Organ Specificity - genetics; Pulmonary arteries; Reproducibility of Results; Studies; Sweden; Technological change; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000754

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