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

doi:10.1016/j.atherosclerosis.2017.09.031

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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

Strawbridge, Rona J. (author)

Silveira, Angela (author)

den Hoed, Marcel (author)

(publisher)

2017
2017
English.
In: Atherosclerosis. - 0021-9150. ; 266, 196-204

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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.

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By the author/editor: Strawbridge, Ron ...; Silveira, Angela; den Hoed, Marcel; Gustafsson, Stef ...; Luan, Jian'an; Rybin, Denis; show more...; Dupuis, Josee; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gadin, Jesper R.; Backlund, Alexan ...; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve ...; Kurl, Sudhir; Langenberg, Clau ...; Lannfelt, Lars; Lind, Lars; Lindgren, Cecili ...; Mannarino, Elmo; Mook-Kanamori, D ...; Morris, Andrew P ...; de Mutsert, Rene ...; Rauramaa, Rainer; Saliba-Gustafsso ...; Sennblad, Bengt; Smit, Andries J.; Syvänen, Ann-Chr ...; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Björn; Bjorck, Hanna M.; Eriksson, Johan ...; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Woute ...; Florez, Jose C.; Wareham, Nichola ...; Meigs, James B.; Ingelsson, Erik; Baldassarre, Dam ...; Hamsten, Anders; show less...

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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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