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- Hägg, Sara, 1977-, et al.
(författare)
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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
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)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<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.
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| 2. |
- Lundström, Jesper
(författare)
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Gene networks and modules in atherosclerosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis we are using global gene expression profiles to unravel functional gene networks and modules. The focus is atherosclerosis, a disease with manifestations in the artery wall where deposits of lipids accumulate and trigger immune responses causing the development of plaques, which upon rupture can lead to a myocardial infarction or stroke. Atherosclerosis is a complex disease influenced by energy metabolism in multiple organs and by several genetic and environmental risk factors. To meet this complexity, we believe the most appropriate approach is to identify gene networks and modules in patients suffering coronary artery disease as well as a relevant mouse model with human-like dyslipidemia prone to atherosclerosis development. First, we investigate structural properties of the regulatory gene network in yeast, integrating protein protein interactions with the transcription network resulting in an estimate the effective gene network underlying gene expression data. In this effective gene network, we show evidence of in-hubs and provide a method for predicting in-hubs directly from gene expression data. In the second study, we used the Ldlr−/− Apob100/100 Mttpflox/flox Mx1-Cre mouse model to study atherosclerosis development and how this development is effected by plasma cholesterollowering. This mouse model has a lipid profile similar to human hyperlipidemia and develops atherosclerosis on a chow diet. Moreover, it contains a genetic switch (Mttpflox/flox Mx1-Cre) to turn off the VLDL synthesis in the liver and lowering plasma cholesterol by > 80%. Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated lipid-poor macrophages accumulated prior the rapid expansion of the plaques. When macrophage concentration reached a critical point it was followed by a rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation also supported by lesion histology. A network of 8 cholesterol-responsive atherosclerosis genes was identified as central to the rapid expansion of the plaques. Third, in the Stockholm Atherosclerosis Gene Expression (STAGE) study, including 124 well-characterized patients undergoing coronary artery bypass surgery, we measured and analyzed 278 expression profiles from the liver, skeletal muscle, mediastinal fat, and aortic lesion (atherosclerotic artery expression with unaffected arterial wall expression subtracted). Clustering of these gene expression profiles performed separately in each organ generated a total of 60 clusters. Two clusters, in aortic lesion (n = 49) and fat (n = 59), related to degree of atherosclerosis. Remarkably, in a validation cohort 27 genes were replicated in a cluster (n =55) also related to the degree of atherosclerosis. In all three clusters relating to atherosclerosis (i.e., the atherosclerosis module), genes in the transendothelial migration of leukocyte pathway (TEML) were overrepresented and the transcription co-factor LIM-domain binding 2 (LDB2) expressed in lesion macrophages and endothelial cells was identified as a potential regulator of this module. In the last study, we first identified 2457 cholesterol-responsive genes in the atherosclerotic arterial wall by lowering plasma cholesterol at 10-weeks intervals during atherosclerosis development using the mouse model of Study II. To prioritize the most atherosclerosis-relevant genes among these 2457, we used a list of 1259 genes active during atherogenesis (Study II) together with three global gene networks generated from human atherosclerosis gene expression profiles in study III, public literature mining, and protein-protein interaction data. Using an integrative network approach to identify genes neighboring any of 68 atherosclerosis seed genes, we identified 35 cholesterol-responsive genes that were believed to be highly relevant to atherosclerosis. Taken together, this thesis provides evidence that systems biological analysis of global gene expression profiles isolated from a wide range of biological specimens can be used to infer functional interactions of genes in modules or networks. The content and architecture of these modules and networks can be used to improve our understanding how complex disorders like atherosclerosis develop.
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