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, AngelaHoed, Marcel denGustafsson, StefanLuan, Jian'anRybin, DenisDupuis, JoséeLi-Gao, RuifangKavousi, MaryamDehghan, AbbasHaljas, KadriLahti, JariGådin, Jesper R.Bäcklund, Alexandrade Faire, UlfGertow, KarlGiral, PhillipeGoel, AnujHumphries, Steve E.Kurl, SudhirLangenberg, ClaudiaLannfelt, Lars L.Lind, LarsLindgren, Cecilia C.M.Mannarino, ElmoMook-Kanamori, Dennis O.Morris, Andrew P.de Mutsert, RenéeRauramaa, RainerSaliba-Gustafsson, PeterSennblad, BengtSmit, Andries J.Syvänen, Ann-ChristineTremoli, ElenaVeglia, FabrizioZethelius, BjörnBjörck, Hanna M.Eriksson, Johan G.Hofman, AlbertFranco, Oscar H.Watkins, HughJukema, J. WouterFlorez, JoseWareham, Nicholas J.Meigs, JamesIngelsson, ErikBaldassarre, DamianoHamsten, Anders2017-12-062017Strawbridge, 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.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493287Background 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.en-USProinsulinAtherosclerosisIntima-media-thicknessSingle nucleotide polymorphismsGenetic variantsMendelian randomisationIdentification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisationJournal Article2017-12-0610.1016/j.atherosclerosis.2017.09.031