| 1. |
- Hägg, Sara, 1977-, et al.
(author)
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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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In: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Journal article (peer-reviewed)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. |
- Sjögren, Per, et al.
(author)
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Autoantibodies against modified apolipoprotein B-100 in relation to low-density lipoprotein size and the metabolic syndrome in otherwise healthy men
- 2008
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In: Metabolism, Clinical and Experimental. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 57:3, s. 362-366
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Journal article (peer-reviewed)abstract
- The role of inflammation in atherosclerotic disease is well established, but the role of autoantibodies against modified apolipoprotein (apo) B-100 remains unclear. The metabolic syndrome is associated with a proinflammatory state, a predominance of small dense low-density lipoprotein (LDL) particles, and an increased risk for atherosclerotic diseases. Previous studies have shown specific autoantibodies against modified apo B-100 (within LDL) to be related to human atherosclerotic disease. The objective of the present study was to investigate whether autoantibodies against modified apo B-100 are related to parameters of the metabolic syndrome, such as small dense LDL. Two hundred ninety-one healthy men were investigated for different metabolic, anthropometric, and inflammatory variables; LDL peak particle size; and distribution of LDL in 4 subfractions. Subjects were grouped according to LDL peak size >= 23.5 nm (pattern A, n = 230) or <23.5 nm (pattern B, n = 61). Immunoglobulin (Ig) G and IgM antibodies against 2 aldehyde-modified peptide sequences, denoted as 45 and 210, within apo B-100 were quantified. Levels of IgG(45), but not the other autoantibodies, were significantly higher in pattern B individuals (with a predominance of small dense LDL particles) compared with pattern A (P < .01). Relationships for both IgG(45) and IgG(210) with parameters typically associated with the metabolic syndrome were found. Only IgG(45) tended to be higher in individuals with the metabolic syndrome compared with those without (P = .07). We conclude that subjects with a predominance of small dense LDL particles have elevated concentrations of IgG(45) in the circulation, which reflect an activated immune response to a specific epitope of modified apo B-100.
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| 3. |
- Sjögren, Per, et al.
(author)
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Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men
- 2007
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In: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 195:2, s. e168-e175
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Journal article (peer-reviewed)abstract
- Endothelial function is considered important in the development of cardiovascular diseases and type 2 diabetes. Circulating advanced glycation end-products (AGEs) and dietary components have been shown to affect endothelial function in type 2 diabetics, but determinants of endothelial function in a non-diabetic population are more poorly investigated. Therefore, we investigated relationships between dietary habits, AGEs and endothelial activation in men with isolated metabolic disturbances. Circulating markers of endothelial activation (soluble forms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor) and plasma N epsilon-carboxymethyl-lysine (CML, the predominant AGE in human plasma) were analyzed in a cross-sectional study of 294 healthy men. Individuals completed a 7-day dietary record, and metabolic and inflammatory parameters were determined. NCEP/ATPIII-criteria were used to define the metabolic syndrome. Endothelial activation was higher in individuals with the metabolic syndrome, and was positively related to certain features of the syndrome (insulin, glucose, inflammation and obesity), but not to others (triacylglycerol and blood pressure). Dietary factors were related to endothelial activation, but CML was not. Multivariate analysis revealed energy and alcohol intake, along with insulin and markers of oxidative stress and inflammation, to be positive predictors of endothelial activation. In this cohort of otherwise healthy men, endothelial activation was increased in individuals with the full metabolic syndrome, but not in those with only some of the components of the metabolic syndrome. Insulin resistance, inflammation, oxidative stress, the dietary intake of energy and alcohol, but not plasma CML, predicted endothelial activation in these men.
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