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

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

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 atheros...

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Bibliographic Details
Main Authors: Strawbridge, RJ, Silveira, A, Hoed, MD, Gustafsson, S, Luan, J, Rybin, D, Dupuis, J, Li-Gao, R, Kavousi, M, Dehghan, A, Haljas, K, Lahti, J, Gådin, JR, Bäcklund, A, de Faire, U, Gertow, K, Giral, P, Goel, A, Humphries, SE, Kurl, S, Langenberg, C, Lannfelt, LL, Lind, L, Lindgren, CCM, Mannarino, E, Mook-Kanamori, DO, Morris, AP, de Mutsert, R, Rauramaa, R, Saliba-Gustafsson, P, Sennblad, B, Smit, AJ, Syvänen, AC, Tremoli, E, Veglia, F, Zethelius, B, Björck, HM, Eriksson, JG, Hofman, A, Franco, OH, Watkins, H, Jukema, JW, Florez, JC, Wareham, NJ, Meigs, JB, Ingelsson, E, Baldassarre, D, Hamsten, A
Format: Journal article
Language:English
Published: Elsevier 2017
Description
Summary: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.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.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.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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