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- Strawbridge, Rona J., et al.
(författare)
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Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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| 2. |
- Saliba Gustafsson, Peter
(författare)
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Characterisation of autophagy pathways in atherosclerosis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis is an inflammatory disease of large to intermediate-sized arteries, characterised by retention of modified low-density lipoprotein within the vessel wall; this evokes an inflammatory response. Low-density lipoprotein carries lipids such as fatty acids, triglycerides and cholesterol, from the liver to peripheral tissues. The lipids carried by lipoproteins can be mobilised for metabolic processes, or if excessive, be stored in intracellular depots called lipid droplets. When imbalances in lipoprotein transport and/or cellular lipid metabolism occur, the risk for metabolic disorders, atherosclerosis and cardiovascular disease increases. Perilipins are lipid droplet-associated proteins, which regulate lipid mobilisation and metabolism from lipid droplets by allowing lipases access to the lipids within the lipid droplet. Macroautophagy, generally referred to as “autophagy”, regulates cholesterol metabolism in macrophage foam cells of atherosclerotic plaques. This is a parallel mechanism by which cells can mobilise lipids, distinct from the traditional dogma that cytosolic lipases mobilise intracellular lipid storages. Further, it contributes to the regulation of inflammation of atherosclerosis-afflicted vessels and it has been shown that ablation of core autophagy genes exacerbates atherosclerosis in murine disease. In this thesis we describe a protein variant in perilipin-2, which reduces plasma triglyceride levels, alters intracellular lipid metabolism and is protective of subclinical atherosclerosis. By adopting a molecular genetic approach, including a well-defined recruit-by-genotype protocol, we clearly demonstrate that perilipin-2 constitutes a hub between cholesterol metabolism and autophagy by fine-tuning liver-X-receptor activity. We also show that liver-X-receptor and autophagy are responsible for their reciprocal activation and that 27-hydroxycholesterol drives this feed-forward loop between liver-X-receptor activity autophagy – the mechanism by which the protein variant in perilipin-2 exerts its beneficial effects on subclinical atherosclerosis. Further we determine the presence of the autophagy-related proteins ATG16L1 and MAP1LC3A in human carotid atherosclerotic plaques where they are associated to plaque inflammation and vascular smooth muscle cell phenotypic switch, respectively. Ultimately, the presence of autophagy-related proteins in human carotid atherosclerotic plaques modulates plaque stability. Collectively, data presented herein, extend on the existing murine data and suggest that deregulated autophagy is a feature of human atherosclerosis. Treatment options targeting autophagy in the treatment of atherosclerosis are still hampered by specificity of treatment and timely intervention.
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