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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
- Source :
- PLoS Genetics, PLoS Genetics, Vol 5, Iss 12, p e1000754 (2009)
- Publication Year :
- 2009
-
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<br />Author Summary The WHO predicts that coronary artery disease (CAD) will become the leading cause of death worldwide in 2010. Currently, major research efforts are focused on understanding the genetics of CAD through multi-center, genome-wide association studies of tens of thousands of patients and controls. Such studies can identify common variants of general importance throughout the entire population, which are likely relatively few. The number of rare genetic variants and variants that act in the context of environmental risk factors for CAD is probably much higher. We performed whole-genome expression analyses in several organs to identify functionally associated genes important for CAD development. We found an atherosclerosis module (A-module) consisting of 128 genes, enriched with genetic risk for CAD, involving transendothelial migration of leukocytes (TEML) and LIM domain binding 2 (LDB2) as its high-hierarchy regulator. Our study design represents a novel way of understanding the molecular underpinnings of CAD, focusing on genome-wide expression sensing both environmental and genetic influences. Investigating the relative enrichment of genetic CAD risk in functional groups (modules and networks) is an alternative approach to extract additional relevant information from genome-wide association studies. The A-module and LDB2 are attractive targets for treatments to modulate TEML and atherosclerosis development.
- Subjects :
- Male
Cancer Research
Pathology
Cardiovascular Disorders/Coronary Artery Disease
Coronary Artery Disease
030204 cardiovascular system & hematology
Coronary artery disease
Cohort Studies
Coronary artery bypass surgery
Mice
0302 clinical medicine
Cell Movement
Gene cluster
Gene expression
Leukocytes
Cluster Analysis
Gene Regulatory Networks
Genetics (clinical)
Regulation of gene expression
0303 health sciences
Genetics and Genomics/Gene Expression
Anatomy
LIM Domain Proteins
3. Good health
Carotid Arteries
Organ Specificity
Female
medicine.symptom
Research Article
medicine.medical_specialty
lcsh:QH426-470
Inflammation
Biology
Computational Biology/Molecular Genetics
03 medical and health sciences
Genetics
medicine
Animals
Humans
Genetic Predisposition to Disease
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Coronary atherosclerosis
030304 developmental biology
Aged
Sweden
Gene Expression Profiling
Computational Biology
Endothelial Cells
Reproducibility of Results
medicine.disease
Atherosclerosis
Gene expression profiling
lcsh:Genetics
Gene Expression Regulation
Transcription Factors
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 5
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS genetics
- Accession number :
- edsair.doi.dedup.....ca213a6e1a7f1a37559fa26076b6b01f