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

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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

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Title: 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
Author: Strawbridge, Rona J.; Silveira, Angela; Hoed, Marcel den; Gustafsson, Stefan; Luan, Jian'an; Rybin, Denis; Dupuis, Josée; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gådin, Jesper R.; Bäcklund, Alexandra; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve E.; Kurl, Sudhir; Langenberg, Claudia; Lannfelt, Lars L.; Lind, Lars; Lindgren, Cecilia C.M.; Mannarino, Elmo; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renée; Rauramaa, Rainer; Saliba-Gustafsson, Peter; Sennblad, Bengt; Smit, Andries J.; Syvänen, Ann-Christine; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Björn; Björck, Hanna M.; Eriksson, Johan G.; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Wouter; Florez, Jose C.; Wareham, Nicholas J.; Meigs, James B.; Ingelsson, Erik; Baldassarre, Damiano; Hamsten, Anders

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Citation: Strawbridge, R. J., A. Silveira, M. d. Hoed, S. Gustafsson, J. Luan, D. Rybin, J. Dupuis, 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 (1): 196-204. doi:10.1016/j.atherosclerosis.2017.09.031. http://dx.doi.org/10.1016/j.atherosclerosis.2017.09.031.
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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.
Published Version: doi:10.1016/j.atherosclerosis.2017.09.031
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679136/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493287
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