| 1. |
- Björkegren, Johan L M, et al.
(författare)
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Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
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| 2. |
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| 3. |
- Franzen, Oscar, et al.
(författare)
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Global analysis of A-to-I RNA editing reveals association with common disease variants
- 2018
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Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- RNA editing modifies transcripts and may alter their regulation or function. In humans, the most common modification is adenosine to inosine (A-to-I). We examined the global characteristics of RNA editing in 4,301 human tissue samples. More than 1.6 million A-to-I edits were identified in 62% of all protein-coding transcripts. mRNA recoding was extremely rare; only 11 novel recoding sites were uncovered. Thirty single nucleotide polymorphisms from genome-wide association studies were associated with RNA editing; one that influences type 2 diabetes (rs2028299) was associated with editing in ARPIN. Twenty-five genes, including LRP11 and PLIN5, had editing sites that were associated with plasma lipid levels. Our findings provide new insights into the genetic regulation of RNA editing and establish a rich catalogue for further exploration of this process.
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| 4. |
- Glicksberg, Benjamin S., et al.
(författare)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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| 5. |
- Hägg, Sara, 1977-, et al.
(författare)
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Carbon-14 Dating to Determine Carotid Plaque Age : Carbon-14 Dating of Carotid Plaques
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Rationale: The exact nature of atherosclerotic plaque development and the molecular mechanisms that lead to clinical manifestations of carotid stenosis are unclear. After nuclear bomb tests in the 1950s, atmospheric 14C concentrations rapidly increased. Since then, the concentrations have been declining, and the curve of declination can be used to date biological samples synthesized during the last five to six decades. Objective: To investigate plaque age as a novel characteristic of atherosclerotic plaques in patients with carotid stenosis. Methods and Results: Carotid plaques from 29 well-characterized endarterectomy patients with symptomatic carotid stenosis were analyzed by accelerator mass spectrometry, and global gene expression of 25 plaque samples was profiled with HG-U133 Plus 2.0 arrays. The average plaque age was 9.3 years, and inter- and intrasample standard variations were low (1–3.5 years); thus, most of the plaques were generated 5–15 years before surgery. Plaque age was not associated with patient age or plaque size, determined by intima-media thickness, but was inversely related to plasma insulin levels (P=0.0014). A cluster of functionally related genes enriched with genes involved in immune responses was activated in plaques with low plaque age, as were oxidative phosphorylation genes. Conclusion: Patients with mild insulin resistance have increased immune and inflammatory gene activity in their carotid plaques causing them to become instable, rapidly progressing into clinical manifestations at a relatively young age. These results show that plaque age, determined by 14C dating, is a novel and important characteristic of atherosclerotic plaques that will improve our understanding of the clinical significance and molecular underpinnings of atherosclerosis.
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| 6. |
- Hägg, Sara, et al.
(författare)
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Carotid Plaque Age Is a Feature of Plaque Stability Inversely Related to Levels of Plasma Insulin
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. e18248-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric C-14-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques. Methodology/Principal Finding: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for C-14 content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6+/-3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p=0.0014). Most plaques were echo-lucent rather than echo-rich (2.2460.97, range 1-5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8+/-12.4 vs. 50.4+/-6.2, p=0.00005; 57.6+/-26.1 vs. 39.8+/-25.7, p<0.0005, respectively), less collagen (45.3+/-6.1 vs. 51.1+/-9.8, p<0.05), and fewer smooth muscle cells (130+/-31 vs. 141+/-21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. Conclusions/Significance: Our results show, for the first time, that plaque age, as judge by relative incorporation of C-14, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.
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| 7. |
- Hägg, Sara, 1977-, et al.
(författare)
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Dual-Specificity Phosphatase-1—An Anti-Inflammatory Marker in Blood Independently Predicting Prolonged Postoperative Stay after Coronary Artery Bypass Grafting : DUSP1 – A Preoperative Blood Marker of Postoperative Stay
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: Perform multi-organ expression profiling to identify gene markers predicting postoperative complications and hospitalization after coronary artery by-pass grafting (CABG) surgery. Background: Identifying patients who are at increased risk of morbidity and prolonged post-operative stay is of interest from both health-economic and individual patient perspectives. Patients with diabetes often present with inflammatory conditions and have prolonged hospitalization after CABG. The recent development of technologies to generate high-dimensional data provides an opportunity to identify preoperative markers that can be used to help optimize preoperative planning to minimize postoperative complications. Methods: We analyzed 198 whole-genome expression profiles of liver, skeletal muscle, and visceral fat isolated from 66 patients undergoing CABG in the Stockholm Atherosclerosis Gene Expression (STAGE) study. The findings were validated in pre-operative blood samples isolated from 181 patients undergoing CABG at Tartu University Hospital. Results: As shown in other studies, diabetic CABG patients in the STAGE cohort also had prolonged hospitalization time (P<0.02). Out of ~50 000 mRNAs measures in the liver, skeletal muscle and visceral fat in 66 STAGE patients, the mRNA levels of anti-inflammatory gene dual specificity phosphatase-1 (DUSP1) correlated independently with post-operative rehabilitation and separated the patients into those with normal (8 days) and prolonged hospitalization (>8 days). In the validation cohort, preoperative blood levels of DUSP1 separated patients with short and long hospitalization stay (P=9x10-10). Conclusions: From genome scans in three separate organs, we identified the anti-inflammatory gene DUSP1 as a pre-operative marker indicating risk for prolonged postoperative stay after CABG.
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| 8. |
- Hägg, Sara, 1977-
(författare)
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Gene Expression Profiling of Human Atherosclerosis
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is a progressive inflammatory disease that causes lipid accumulation in the arterial wall, leading to the formation of plaques. The clinical manifestations of plaque rupture—stroke and myocardial infarction—are increasing worldwide and pose an enormous economic burden for society. Atherosclerosis development reflects a complex interaction between environmental exposures and genetic predisposition. To understand this complexity, we hypothesized that a top-down approach—one in which all molecular activities that drive atherosclerosis are examined simultaneously—is necessary to highlight those that are clinically relevant. To this end, we performed whole-genome expression profiling in multiple tissues isolated from patients with coronary artery disease (CAD).In the Stockholm Atherosclerosis Gene Expression (STAGE) study, biopsies of five tissues (arterial wall with and without atherosclerotic lesions, liver, skeletal muscle and visceral fat) were isolated from 124 CAD patients undergoing coronary artery bypass grafting surgery (CABG) at the Karolinska University Hospital, Solna and carotid lesions from 39 patients undergoing carotid artery surgery at Stockholm Söder Hospital. Detailed clinical characteristics of these patients were assembled together with a total of 303 global gene expression profiles obtained with the Affymetrix GeneChip platform.In paper 1, a two-way clustering analysis of the data identified 60 tissue clusters of functionally related genes. One cluster, partly present in both visceral fat and atherosclerotic lesions, related to atherosclerosis severity as judged by coronary angiograms. Many of the genes in that cluster were also present in a carotid lesion cluster relating to intima-media thickness (IMT) in the carotid patients. The union of all three clusters relating to extent of atherosclerosis—referred to as the “A-module”—was overrepresented with genes belonging to the transendothelial migration of leukocyte (TEML) pathway. The transcription co-factor, Lim domain binding 2 (LDB2), was identified as putative regulator of the A-module and TEML pathway in validation studies including Ldb2-/- mice.In paper 2, we investigated the increased incidence of postoperative complications in CABG patients with diabetes. Using the STAGE compendium, we identified an anti-inflammatory marker, dual-specificity phosphatase 1 (DUSP1), as a novel preoperative blood marker of risk for a prolonged hospital stay after CABG.In paper 3, plaque age was determined with C14-dating in the carotid patients. Interestingly, the strongest correlation with plaque age was not the age of the patients or IMT. Rather, the strongest correlations were with plasma insulin levels and inflammatory gene expression.Taken together, the findings in this thesis show that a top-down approach using multi-tissue gene expression profiling in CAD and C14-dating of plaques can contribute to a better understanding of the molecular processes underlying atherosclerosis development and to the identification of clinically useful biomarkers.
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| 9. |
- Hägg, Sara, et al.
(författare)
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Molecular Phenotypes of Coronary Artery Disease : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUNDBy offering a comprehensive view of the molecular underpinnings of pathology, high-dimensional data have the potential to revolutionize the diagnosis and management of complex disorders such as coronary artery disease (CAD). To identify molecular phenotypes of CAD, we performed multi organ gene expression profiling of subjects enrolled in the Stockholm Atherosclerosis Gene Expression (STAGE) study.METHODSAtherosclerotic and unaffected arterial wall, liver, skeletal muscle, and mediastinal fat biopsies were obtained during coronary artery bypass grafting from 114 well-characterized CAD patients. RNA samples were isolated, and 278 transcription profiles were obtained using Affymetrix HG-U133_Plus_2 GeneChips.RESULTSThe most prominent molecular phenotype of the CAD patients was represented by 733 genes in mediastinal fat, which were involved in extracellular matrix organization, response to stress and regulation of programmed cell death. Other aspects of this phenotype were shared with liver (e.g., oxidoreductase activity), skeletal muscle (insulin-like growth factor binding), and atherosclerotic arterial wall (cell motility and adhesion, fatty acid metabolism). In addition, the activity of 400 genes exclusively in mediastinal fat was associated with the extent of coronary stenosis and atherosclerosis. Immune-cell activation in mediastinal fat defined CAD patients with poor blood glucose control and prolonged hospitalization.CONCLUSIONSThe molecular phenotype of mediastinal fat appears to be central in CAD and should be useful for early identification of CAD risk.
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| 10. |
- 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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| 11. |
- Krämer, David Kitz, et al.
(författare)
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Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor delta
- 2005
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Ingår i: Diabetes. - Alexandria, USA : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:4, s. 1157-1163
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Tidskriftsartikel (refereegranskat)abstract
- Activators of peroxisome proliferator-activated receptor (PPAR)gamma have been studied intensively for their insulin-sensitizing properties and antidiabetic effects. Recently, a specific PPARdelta activator (GW501516) was reported to attenuate plasma glucose and insulin levels when administered to genetically obese ob/ob mice. This study was performed to determine whether specific activation of PPARdelta has direct effects on insulin action in skeletal muscle. Specific activation of PPARdelta using two pharmacological agonists (GW501516 and GW0742) increased glucose uptake independently of insulin in differentiated C2C12 myotubes. In cultured primary human skeletal myotubes, GW501516 increased glucose uptake independently of insulin and enhanced subsequent insulin stimulation. PPARdelta agonists increased the respective phosphorylation and expression of AMP-activated protein kinase 1.9-fold (P < 0.05) and 1.8-fold (P < 0.05), of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) 2.2-fold (P < 0.05) and 1.7-fold (P < 0.05), and of p38 MAPK 1.2-fold (P < 0.05) and 1.4-fold (P < 0.05). Basal and insulin-stimulated protein kinase B/Akt was unaltered in cells preexposed to PPARdelta agonists. Preincubation of myotubes with the p38 MAPK inhibitor SB203580 reduced insulin- and PPARdelta-mediated increase in glucose uptake, whereas the mitogen-activated protein kinase kinase inhibitor PD98059 was without effect. PPARdelta agonists reduced mRNA expression of PPARdelta, sterol regulatory element binding protein (SREBP)-1a, and SREBP-1c (P < 0.05). In contrast, mRNA expression of PPARgamma, PPARgamma coactivator 1, GLUT1, and GLUT4 was unaltered. Our results provide evidence to suggest that PPARdelta agonists increase glucose metabolism and promote gene regulatory responses in cultured human skeletal muscle. Moreover, we provide biological validation of PPARdelta as a potential target for antidiabetic therapy.
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| 12. |
- Nilsson, Kristoffer, et al.
(författare)
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Model-based predictions on health benefits and budget impact of implementing empagliflozin in people with type 2 diabetes and established cardiovascular disease
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 25:3, s. 748-757
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To perform a model-based analysis of the short- and long-term health benefits and costs of further increased implementation of empagliflozin for people with type 2 diabetes and established cardiovascular disease (eCVD) in Sweden.MATERIALS AND METHODS: The validated Institute for Health Economics Diabetes Cohort Model (IHE-DCM) was used to estimate health benefits and 3-years' budget impact, and lifetime costs per quality-adjusted life year (QALY) gained of increased implementation of adding empagliflozin to standard of care (SoC) for people with type 2 diabetes and eCVD in a Swedish setting. Scenarios with 100%/75%/50% implementation were explored. Analyses were based on 30 model cohorts with type 2 diabetes and eCVD (n=131,412 at baseline) from national health data registers. Sensitivity analyses explored the robustness of results.RESULTS: Over 3 years, SoC with empagliflozin (100% implementation) vs. SoC before empagliflozin resulted in 7,700 total life years gained and reductions in cumulative incidence of cardiovascular deaths by 30% and heart failures by 28%. Annual costs increased by 6% from higher treatment costs and increased survival. Half of these benefits and costs are not yet reached with current implementation below 50%. SoC with empagliflozin yielded 0.37 QALYs per person, with an incremental cost-effectiveness ratio of €16,000 EUR per QALY vs. SoC before empagliflozin.CONCLUSIONS: Model simulations using real-world data and trial treatment effects indicated that a broader implementation of empagliflozin, in line with current guidelines for treatment of people with type 2 diabetes and eCVD, would lead to further benefits even in a short-term perspective.
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| 13. |
- Persson, Sofie, et al.
(författare)
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Burden of established cardiovascular disease in people with type 2 diabetes and matched controls : Hospital-based care, days absent from work, costs, and mortality
- 2023
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 53:3, s. 726-734
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To assess hospital-based care, work absence, associated costs, and mortality in type 2 diabetes with and without established cardiovascular disease (eCVD) compared to matched controls.METHODS: In a population-based cohort study, we analysed individual-level data from national health, social insurance, and socio-economic registers for people with type 2 diabetes diagnosis<70 years and controls (5:1) in Sweden. Regression analysis attributed costs and days absent to eCVD. Mortality was analysed using Cox proportional hazard regression stratified for birthyear and adjusted for sex and education.RESULTS: Thirty percent (n=136 135 of 454 983) of people with type 2 diabetes had ≥1 person-year with eCVD (women 24%; men 34%). The mean annual costs of hospital-based care for diabetes complications were EUR 2 629 (95% confidence interval [CI] 2 601 to 2 657) of which EUR 2 337 (95% CI 2 309 to 2 365) were attributed to eCVD (89%). The highest-costing person-years (10th percentile) were observed in a broad subgroup, 42% of people with type 2 diabetes and eCVD. People with type 2 diabetes had on average 146 days absent (95% CI 145-147) per year of which 68 days (47%; 95% CI 67-70) were attributed to eCVD. Mortality was increased in type 2 diabetes: eCVD hazard rate [HR] 4.63 (95% CI 4.58-4.68), no eCVD HR 1.86 (95% CI 1.84-1.88).CONCLUSIONS: The sizable burden of eCVD, on the individual with type 2 diabetes and the society, calls for efficient management for reducing the risks for those living with eCVD and postponing its onset. This article is protected by copyright. All rights reserved.
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| 14. |
- Shang, Ming-Mei, et al.
(författare)
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Lim domain binding 2 : a key driver of transendothelial migration of leukocytes and atherosclerosis
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 34:9, s. 2068-2077
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Using a multi-tissue, genome-wide gene expression approach, we recently identified a gene module linked to the extent of human atherosclerosis. This atherosclerosis module was enriched with inherited risk for coronary and carotid artery disease (CAD) and overlapped with genes in the transendothelial migration of leukocyte (TEML) pathway. Among the atherosclerosis module genes, the transcription cofactor Lim domain binding 2 (LDB2) was the most connected in a CAD vascular wall regulatory gene network. Here, we used human genomics and atherosclerosis-prone mice to evaluate the possible role of LDB2 in TEML and atherosclerosis.APPROACH AND RESULTS: mRNA profiles generated from blood macrophages in patients with CAD were used to infer transcription factor regulatory gene networks; Ldlr(-/-)Apob(100/100) mice were used to study the effects of Ldb2 deficiency on TEML activity and atherogenesis. LDB2 was the most connected gene in a transcription factor regulatory network inferred from TEML and atherosclerosis module genes in CAD macrophages. In Ldlr(-/-)Apob(100/100) mice, loss of Ldb2 increased atherosclerotic lesion size ≈2-fold and decreased plaque stability. The exacerbated atherosclerosis was caused by increased TEML activity, as demonstrated in air-pouch and retinal vasculature models in vivo, by ex vivo perfusion of primary leukocytes, and by leukocyte migration in vitro. In THP1 cells, migration was increased by overexpression and decreased by small interfering RNA inhibition of LDB2. A functional LDB2 variant (rs10939673) was associated with the risk and extent of CAD across several cohorts.CONCLUSIONS: As a key driver of the TEML pathway in CAD macrophages, LDB2 is a novel candidate to target CAD by inhibiting the overall activity of TEML.
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| 15. |
- Skogsberg, Josefin
(författare)
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PPAR delta : its role in cholesterol metabolism
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors that regulate several biological processes, many of which are crucial for energy homeostasis. Three different isotypes have been identified; PPARalpha, PPARdelta and PPARgamma that are encoded by different genes and show different expression patterns and functions. PPARalpha controls the expression of genes involved in the catabolism wheras PPARgamma control genes involved in the storage of fatty acids. The role of PPARdelta is not yet fully elucidated although the work presented in this thesis provides evidence that PPARdelta is implicated in cholesterol metabolism in humans. To better understand the role of PPARdelta in human physiology the structure and expression pattern of the gene was determined. The PPARdelta gene spans approximately 85 kilobases (kb) of DNA and consists of nine exons. Exons 1-3, the 5'-part of exon 4 and the 3'part of exon 9 are untranslated. The TATA box-less gene is transcribed from a unique start site located 380 base pairs (bp) upstream of the ATG initiation codon. PPARdelta is ubiquitously expressed and its mRNA size is 3.8 kb. Radiation hybrid mapping located the PPARdelta gene at chromosomal region 6p21.2. In order to explore the role of PPARdelta in human cholesterol metabolism we searched for functional polymorphisms in the 5'-region of the gene to use as a tool in association studies. Of four polymorphisms found only the +294T/C variant in exon 4, located 86 bp upstream of the translation start site, showed an association with a metabolic trait in two independent cohorts of healthy middle-aged men. Homozygotes for the rare C-allele had higher plasma LDL-cholesterol concentration than homozygotes for the common T-allele. Transient transfection studies showed that the C-allele conferred higher transcriptional activity than the common Tallele. Whether the +294C allele is associated with LDL-cholesterol elevation independently of the background lipoprotein phenotype and whether it results in increased risk of coronary heart disease (CHD) was investigated in the West of Scotland Coronary Prevention Study (WOSCOPS). WOSCOPS is a prospective double-blind placebo controlled study designed to assess the value of pravastatin treatment in the prevention of CHD events in moderately hypercholesterolaemic men. Individuals carrying the rare PPARdelta +294C allele had significantly lower plasma HDL-cholesterol concentrations and showed a tendency towards higher risk of CHD than subjects homozygous for the common T-allele. To identify genes involved in cholesterol metabolism that are regulated by PPARdelta, a potent selective agonist was synthesized. Hepatic cells treated with the agonist showed decreased expression of the LDL receptor gene as measured by microarray and TaqMan analyses. EMSAs identified two potential PPAR response elements in the LDL receptor promoter, suggesting that the effect of PPARdelta on LDL receptor gene expression may be direct. Thus, one might speculate that the increase in plasma LDL-cholesterol concentration observed in the association studies could partly be explained by a reduction in LDL receptor expression. Taken together, these studies provide evidence that PPARdelta is implicated in cholesterol metabolism and suggest that the receptor plays an atherogenic role in healthy humans.
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| 16. |
- Skogsberg, Josefin, et al.
(författare)
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Whole-genome expression profiling of human plaques to identify genes relevant for atherosclerosis : the Stockholm Atherosclerosis Gene Expression Study, Stockholm Söder Hospital, Sweden (SöS-STAGE)
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectiveTo reveal relevant genes for atherosclerosis by whole-genome expression analyses of plaques from patients undergoing carotid endorectomy.Methods and ResultsWhole-genome expression measurements (WGEM) using Affymetrix HG-U133_Plus_2 chip of carotid plaques in patients undergoing carotid endorectomy at Stockholm Söder Hospital, Sweden. Patients were screened for conventional risk factors at a three-month follow-up visit and atherosclerosis burden in the common carotid artery (CCA) was measured by intima-media thickness (IMT). An unsupervised coupled two-way clustering approach identified genderspecific genes and 55 genes associated to degree of IMT in these patients.ConclusionsCoupled two-way clustering of carotid lesion expression profiles from a well-characterized clinical cohort is useful for identification of novel genes that may be relevant for atheroscleroris.
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| 17. |
- Tegnér, Jesper, 1962-, et al.
(författare)
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Multi-organ whole-genome measurements and reverse engineering to uncover gene networks underlying complex traits
- 2007
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 48:2, s. 267-277
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Together with computational analysis and modeling, the development of whole-genome measurement technologies holds the potential to fundamentally change research on complex disorders such as coronary artery disease. With these tools, the stage has been set to reveal the full repertoire of biological components (genes, proteins, and metabolites) in complex diseases and their interplay in modules and networks. Here we review how network identification based on reverse engineering, as applied to whole-genome datasets from simpler organisms, is now being adapted to more complex settings such as datasets from human cell lines and organs in relation to physiological and pathological states. Our focus is on the use of a systems biological approach to identify gene networks in coronary atherosclerosis. We also address how gene networks will probably play a key role in the development of early diagnostics and treatments for complex disorders in the coming era of individualized medicine. Copyright ©2007 by the American Society for Biochemistry and Molecular Biology, Inc.
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| 18. |
- Wågsäter, Dick, et al.
(författare)
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MMP-2 and MMP-9 are prominent matrix metalloproteinases during atherosclerosis development in the LdlrApob100/100 mouse
- 2011
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Ingår i: International Journal of Molecular Medicine. - : Spandidos Publications. - 1107-3756 .- 1791-244X. ; 28:2, s. 247-253
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Tidskriftsartikel (refereegranskat)abstract
- Matrix-degrading proteases capable of degrading components of the extracellular matrix may play an important role in development and progression of atherosclerotic lesions. In the present study, we used the Ldlr(-/-)Apob(100/100) mouse model, which has a plasma lipoprotein profile similar to that of humans with atherosclerosis, to study the expression of matrix metalloproteinases (MMPs) during early stages of atherosclerosis development. We analyzed the expression of 11 proteases and three protease inhibitors in 5- to 40-week-old Ldlr(-/-)Apob(100/100) mice. Expression and activity of MMP-2 and MMP-9 was increased in advanced atherosclerotic lesions followed by macrophage infiltration as shown by real-time PCR, gel-based and in situ zymography and immunohistochemistry. Expression of other investigated MMPs did not increase during disease progression. However, the mRNA expression of MMP-8 and MMP-13 was down-regulated, which could explain the relatively high amount of collagen observed in the vessels in this model. In conclusion, low proteolytic expression at early stages of atherogenesis and a limited repertoire of proteolytic enzymes were associated with the progression of atherosclerosis in Ldlr(-/-)Apob(100/100) mice. The study suggests that MMP-2 and MMP-9 are the main proteases involved in atherogenesis in this mouse model.
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