| 1. |
- Hägg, Daniel, 1974, et al.
(författare)
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Expression of chemokine (C-C motif) ligand 18 in human macrophages and atherosclerotic plaques
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 204:2, s. e15-20
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Using gene expression profiling, we aimed to identify genes that are predominantly expressed in human carotid atherosclerotic plaques. Such genes may be important in atherogenesis and pathophysiology of the plaque, and genes that encode for secreted proteins may be potential biomarkers for atherosclerosis and cardiovascular disease. METHODS: DNA microarray generated expression profiles of human carotid atherosclerotic plaques were compared to expression profiles of 80 different human tissues and cell types, to identify plaque-specific genes. RESULTS: We identified the chemokine (C-C motif) ligand 18 (CCL18) as predominantly expressed in human carotid plaque. Immunohistochemistry showed that CCL18 protein was localized to a subset of macrophages in carotid plaques. Monocyte-derived macrophages from subjects with atherosclerosis had threefold higher expression of CCL18 than macrophages from control subjects (p=0.012). Subjects with A/G genotype of the rs2015086 SNP in the promoter region of the CCL18 gene had threefold higher macrophage expression of CCL18 than subjects with A/A genotype (p=0.049), but we found no association of this SNP with an increased risk of coronary heart disease. We also compared serum levels of CCL18 from subjects with symptomatic carotid artery disease with control subjects. There were no differences in serum levels of CCL18 between the two groups, however CCL18 correlated with measurements of adiposity. CONCLUSION: CCL18 is predominantly expressed in human atherosclerotic plaques and may participate in the atherosclerotic plaque formation.
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| 2. |
- Hägg, Daniel, 1974, et al.
(författare)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
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Ingår i: International journal of molecular medicine. - 1107-3756. ; 21:6, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 3. |
- Olofsson, Louise, 1977, et al.
(författare)
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Preliminary report: Zn-alpha2-glycoprotein genotype and serum levels are associated with serum lipids.
- 2010
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Ingår i: Metabolism. - : Elsevier BV. - 1532-8600 .- 0026-0495. ; 59:9, s. 1316-1318
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Tidskriftsartikel (refereegranskat)abstract
- Zn-alpha2-glycoprotein (ZAG) is a serum protein implicated in cancer cachexia and lipolysis. Our aim was to investigate serum levels of ZAG and polymorphisms in the ZAG gene in relation to serum lipids in man. Serum levels of ZAG correlated with serum levels of cholesterol (P = .00088) in healthy subjects and during weight loss (P = .059). The ZAG genotype was associated with total cholesterol (P = .014) and low-density lipoprotein cholesterol (P = .026) in healthy subjects, and the associations were replicated in an additional cohort (P = .0017 and P = .060, respectively). Our data indicate that ZAG plays a role in lipid metabolism.
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| 4. |
- Olsson, Bob, 1969, et al.
(författare)
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Apolipoprotein C-I genotype and serum levels of triglycerides, C-reactive protein and coronary heart disease
- 2010
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Ingår i: Metabolism. - : Elsevier BV. - 0026-0495. ; 59:12, s. 1736-1741
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein C-I (apoCI) is implicated in lipid metabolism and inflammatory response, both important risk factors for human heart disease. However, most findings come from in vitro or animal studies, whereas data on human apoCI are sparse. To elucidate the role of apoCI in human disease, we analyzed a functional polymorphism in the promoter region of the apoCI gene in relation to blood lipids, C-reactive protein (CRP), coronary artery disease (CAD), and myocardial infarction (MI). Rs11568822 is a 4-base pair insertion/deletion (Ins/Del) polymorphism, and the Ins allele leads to a higher transcription in vitro compared with the Del allele. This polymorphism was analyzed in the Intergene study, a case-control study for CAD (N = 1236), and the Stockholm Heart Epidemiology Program, a case-control study for MI (N = 2774). Subjects homozygous for the Ins genotype had significantly higher serum levels of triglycerides (P = .01 and P = .006) and lower serum levels of CRP (P = .02 and P < .0001) compared with all other subjects in both studies. Similar results were obtained when analyzing only the controls of both studies (P = .002 and P = .0002, triglycerides; P = .002 and P < .0001, CRP). However, apoCI was not associated with CAD or MI. In conclusion, our data show that apoCI genotype is associated with serum levels of triglycerides and CRP, confirming the role of apoCI in lipid metabolism and suggesting that it also influences inflammation.
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| 5. |
- Olsson, Maja, 1975, et al.
(författare)
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Expression of the selenoprotein S (SELS) gene in subcutaneous adipose tissue and SELS genotype are associated with metabolic risk factors.
- 2011
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 60:1, s. 114-20
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Tidskriftsartikel (refereegranskat)abstract
- The selenoprotein S (SELS) is a putative receptor for serum amyloid A, and recent studies have suggested that SELS may be a link between type 2 diabetes mellitus and inflammation. Genetic studies of SELS polymorphisms have revealed associations with circulating levels of inflammatory markers and hard end points of cardiovascular disease. In this study, we analyzed SELS expression in subcutaneous adipose tissue and SELS genotype in relation to metabolic risk factors. DNA microarray expression analysis was used to study the expression of SELS in lean and obese siblings from the Swedish Obese Subjects Sib Pair Study. TaqMan genotyping was used to analyze 3 polymorphisms, previously found to be associated with circulating levels of inflammatory markers, in the INTERGENE case-control study of myocardial infarction and unstable angina pectoris. Possible associations between SELS genotype and/or expression with anthropometry and measures of metabolic status were investigated. Real-time polymerase chain reaction was used to analyze the SELS expression in isolated human adipocytes incubated with insulin. In lean subjects, we found correlations between SELS gene expression in subcutaneous adipose tissue and measures of obesity (waist, P = .045; sagittal diameter, P = .031) and blood pressure (diastolic, P = .016; systolic P = .015); and in obese subjects, we found correlations with measures of obesity (body mass index, P = .03; sagittal diameter, P = .008) and glycemic control (homeostasis model assessment of insulin resistance, P = .011; insulin, P = .009) after adjusting for age and sex. The 5227GG genotype was associated with serum levels of insulin (P = .006) and homeostasis model assessment of insulin resistance (P = .007). The expression of SELS increased after insulin stimulation in isolated human adipocytes (P = .008). In this study, we found an association between both SELS gene expression in adipose tissue and SELS genotype with measures of glycemic control. In vitro studies demonstrated that the SELS gene is regulated by insulin in human subcutaneous adipocytes. This study further supports a role for SELS in the development of metabolic disease, especially in the context of insulin resistance.
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| 6. |
- Svensson, Per-Arne, 1969, et al.
(författare)
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Regulation and splicing of scavenger receptor class B type I in human macrophages and atherosclerotic plaques
- 2005
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Ingår i: BMC Cardiovasc Disord. - : Springer Science and Business Media LLC. - 1471-2261. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The protective role of high-density lipoprotein (HDL) in the cardiovascular system is related to its role in the reverse transport of cholesterol from the arterial wall to the liver for subsequent excretion via the bile. Scavenger receptor class B type I (SR-BI) binds HDL and mediates selective uptake of cholesterol ester and cellular efflux of cholesterol to HDL. The role of SR-BI in atherosclerosis has been well established in murine models but it remains unclear whether SR-BI plays an equally important role in atherosclerosis in humans. The aim of this study was to investigate the expression of SR-BI and its isoforms in human macrophages and atherosclerotic plaques. METHODS: The effect of hypoxia and minimally modified low-density lipoprotein (mmLDL), two proatherogenic stimuli, on SR-BI expression was studied in human monocyte-derived macrophages from healthy subjects using real-time PCR. In addition, SR-BI expression was determined in macrophages obtained from subjects with atherosclerosis (n = 15) and healthy controls (n = 15). Expression of SR-BI isoforms was characterized in human atherosclerotic plaques and macrophages using RT-PCR and DNA sequencing. RESULTS: SR-BI expression was decreased in macrophages after hypoxia (p < 0.005). In contrast, SR-BI expression was increased by exposure to mmLDL (p < 0.05). There was no difference in SR-BI expression in macrophages from patients with atherosclerosis compared to controls. In both groups, SR-BI expression was increased by exposure to mmLDL (p < 0.05). Transcripts corresponding to SR-BI and SR-BII were detected in macrophages. In addition, a third isoform, referred to as SR-BIII, was discovered. All three isoforms were also expressed in human atherosclerotic plaque. Compared to the other isoforms, the novel SR-BIII isoform was predicted to have a unique intracellular C-terminal domain containing 53 amino acids. CONCLUSION: We conclude that SR-BI is regulated by proatherogenic stimuli in humans. However, we found no differences between subjects with atherosclerosis and healthy controls. This indicates that altered SR-BI expression is not a common cause of atherosclerosis. In addition, we identified SR-BIII as a novel isoform expressed in human macrophages and in human atherosclerotic plaques.
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