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 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 A-C., 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.
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.