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, R. J. et al. (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. (doi:10.1016/j.atherosclerosis.2017.09.031) (PMID:29040868)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strawbridge, Dr Rona
Authors: Strawbridge, R. J., Silveira, A., den Hoed, M., Gustafsson, S., Luan, J.’a., Rybin, D., Dupuis, J., Li-Gao, R., Kavousi, M., Dehghan, A., Haljas, K., Lahti, J., Gådin, J. R., Bäcklund, A., de Faire, U., Gertow, K., Giral, P., Goel, A., Humphries, S. E., Kurl, S., Langenberg, C., Lannfelt, L. L., Lind, L., Lindgren, C. C.M., Mannarino, E., Mook-Kanamori, D. O., Morris, A. P., de Mutsert, R., Rauramaa, R., Saliba-Gustafsson, P., Sennblad, B., Smit, A. J., Syvänen, A.-C., Tremoli, E., Veglia, F., Zethelius, B., Björck, H. M., Eriksson, J. G., Hofman, A., Franco, O. H., Watkins, H., Jukema, J. W., Florez, J. C., Wareham, N. J., Meigs, J. B., Ingelsson, E., Baldassarre, D., and Hamsten, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Atherosclerosis
Publisher:Elsevier
ISSN:0021-9150
ISSN (Online):1879-1484
Published Online:28 September 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Atherosclerosis 266: 196-204
Publisher Policy:Reproduced under a Creative Commons License

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