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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
Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Univ Glasgow, Inst Mental Hlth & Wellbeing, Mental Hlth & Wellbeing, Glasgow, Lanark, Scotland.;Univ Glasgow, Dept Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland..
Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-8081-428X
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
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2017 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 266, p. 196-204
Keywords [en]
Proinsulin, Atherosclerosis, Intima-media-thickness, Single nucleotide polymorphisms, Genetic variants, Mendelian randomisation
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-341363DOI: 10.1016/j.atherosclerosis.2017.09.031ISI: 000414069700027PubMedID: 29040868OAI: oai:DiVA.org:uu-341363DiVA, id: diva2:1181397
Funder
Swedish Research Council, 8691 09533 2012-1397 2015-03657Swedish Heart Lung Foundation, 20120197 20140543EU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Stockholm County Council, 592229EU, FP7, Seventh Framework Programme, IMI/115006Swedish National Infrastructure for Computing (SNIC), b2011036Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved

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