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



Strawbridge, Rona J, Silveira, Angela, den Hoed, Marcel, Gustafsson, Stefan, Luan, Jian'an, Rybin, Denis, Dupuis, Josee, Li-Gao, Ruifang, Kavousi, Maryam, Dehghan, Abbas
et al (show 38 more authors) (2017) 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. ATHEROSCLEROSIS, 266. pp. 196-204.

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Abstract

<h4>Background and aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 IMT<sub>mean</sub> and IMT<sub>max</sub> (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.<h4>Conclusions</h4>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.

Item Type: Article
Uncontrolled Keywords: Proinsulin, Atherosclerosis, Intima-media-thickness, Single nucleotide polymorphisms, Genetic variants, Mendelian randomisation
Depositing User: Symplectic Admin
Date Deposited: 03 Nov 2017 13:27
Last Modified: 19 Jan 2023 06:51
DOI: 10.1016/j.atherosclerosis.2017.09.031
Open Access URL: http://www.sciencedirect.com/science/article/pii/S...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3011424