| 1. |
|
|
| 2. |
- Franzen, Oscar, et al.
(författare)
-
Global analysis of A-to-I RNA editing reveals association with common disease variants
- 2018
-
Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 6
-
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.
|
|
| 3. |
- Glicksberg, Benjamin S., et al.
(författare)
-
Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
-
Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
-
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.
|
|
| 4. |
- Hägg, Sara, et al.
(författare)
-
Carotid Plaque Age Is a Feature of Plaque Stability Inversely Related to Levels of Plasma Insulin
- 2011
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. e18248-
-
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.
|
|
| 5. |
- Hägg, Sara, 1977-, et al.
(författare)
-
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
-
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.
|
|
| 6. |
- Jones, Gregory T., et al.
(författare)
-
Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci
- 2017
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 120:2, s. 341-
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease.
|
|
| 7. |
- Kleeman, Sam O, et al.
(författare)
-
Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy.
- 2023
-
Ingår i: Cell genomics. - 2666-979X. ; 3:8
-
Tidskriftsartikel (refereegranskat)abstract
- Cystatin C (CyC), a secreted cysteine protease inhibitor, has unclear biological functions. Many patients exhibit elevated plasma CyC levels, particularly during glucocorticoid (GC) treatment. This study links GCs with CyC's systemic regulation by utilizing genome-wide association and structural equation modeling to determine CyC production genetics in the UK Biobank. Both CyC production and a polygenic score (PGS) capturing predisposition to CyC production were associated with increased all-cause and cancer-specific mortality. We found that the GC receptor directly targets CyC, leading to GC-responsive CyC secretion in macrophages and cancer cells. CyC-knockout tumors displayed significantly reduced growth and diminished recruitment of TREM2+ macrophages, which have been connected to cancer immunotherapy failure. Furthermore, the CyC-production PGS predicted checkpoint immunotherapy failure in 685 patients with metastatic cancer from combined clinical trial cohorts. In conclusion, CyC may act as a GC effector pathway via TREM2+ macrophage recruitment and may be a potential target for combination cancer immunotherapy.
|
|
| 8. |
- Morgan, Ruth A., et al.
(författare)
-
Carbonyl reductase 1 catalyzes 20 beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity
- 2017
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.
|
|
| 9. |
- Ruusalepp, Arno
(författare)
-
Signal transduction in restenosis and myocardial protection by hyperoxia
- 2006
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ischemic heart disease is a major cause of morbidity and mortality in the western world. Revascularization of ischemic myocardium is essential for cell survival, and is performed by thrombolysis, percutaneous transluminal coronary angioplasty (PTCA) and by coronary artery bypass grafting. However, revascularization may paradoxically exacerbate ischemic injury, and it is desirable to develop strategies reducing this. One possible way is by evoking myocardial protection through exposure to oxygen. Revascularization by PTCA often has a poor outcome, as 20-40% of the arteries will restenose. Signal transduction pathways involving nuclear factor kappa B (NF-kappaB) have been implicated in neointima formation. However, a limitation of many experimental studies is the use of animals with healthy vessels. To improve the treatment of ischemic heart disease and restenosis, it is necessary to understand the molecular basis of disease. The present papers explore molecular mechanisms of these phenomena, with the perspective of developing future therapies. METHODS. Carotid artery injury was induced by separate ligation of the external and internal branch. NF-kappaB activation was assessed by NF-kappaB controlled reporter gene activation in transgenic mice. Neointima formation was evaluated in mice with genetical deletion of the NF-kappaB p105 subunit (p50 precursor) and the corresponding wild types. Apolipoprotein E/LDL receptor double knockout mice (ApoE/LDLr KO), which develop atherosclerosis, were fed an atherogenic diet three months prior to experiments and lesions compared to those of wild types. For studies of heart physiology, mice or rats were exposed to different concentrations of oxygen, thereafter their hearts exised and perfused with induced global ischemia. RESULTS (papers 1 & 2). Carotid artery ligation lead to formation of neointima four weeks later and induced NF-kappaB activation in the injured vessel OBS wall. Neointima lesions were larger in p105 KO than in wild types. NF-kappaB activation was accompanied by increased expression of inflammatory genes and basic fibroblast growth factor (real time PCR). NF-kappaB p105 knockout mice had reduced expression of the inflammatory genes and a higher percentage of basic fibroblasts growth factor positive cells. The shape and size of the lesions were reproducible in both ApoE/LDLr KO and wild types. The inflammatory reaction was more persistent in lesions from atherosclerotic mice. (Papers 3 & 4): In vivo exposure to oxygen before heart isolation improved heart function and reduced infarct size, but the protection was dependent on exposure time and oxygen concentration, and was different in rats and mice. In mice hyperoxic exposure caused cardiac phosphorylation of the mitogen activated protein kinases p38 and ERK1/2, but not JNK. The NOS-inhibitor L-NAME, the ERK1/2 inhibitor PD98059, and the p38 inhibitor FR167653 all reduced the protection afforded by hyperoxic exposure. CONCLUSION. Activation of the p105 subunit of NF-kappaB as a response to arterial injury may be a key regulator of the inflammatory response to injury and essential for tissue repair. We established a reproducible model of arterial injury with neointima formation in atherosclerotic mice. Hyperoxia protects the isolated rat and mouse heart against ischemia-reperfusion injury. The protection depended on both oxygen concentration in inspired air and the duration of hyperoxic exposure. Nitric oxide triggers or mediates hyperoxic protection, and ERK1/2 and p38 MAPK are involved in signalling of protection against ischemia-reperfusion injury.
|
|
| 10. |
- Shang, Ming-Mei, et al.
(författare)
-
Lim domain binding 2 : a key driver of transendothelial migration of leukocytes and atherosclerosis
- 2014
-
Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1079-5642 .- 1524-4636. ; 34:9, s. 2068-2077
-
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.
|
|
