1. 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
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Strawbridge, R.J., Silveira, A., Hoed, M. den, Gustafsson, S., Luan, J.A., Rybin, D., Dupuis, J., Li-Gao, R.F., Kavousi, M., Dehghan, A., Haljas, K., Lahti, J., Gadin, J.R., Backlund, A., Faire, U. de, 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., Mutsert, R. de, Rauramaa, R., Saliba-Gustafsson, P., Sennblad, B., Smit, A.J., Syvanen, A.C., Tremoli, E., Veglia, F., Zethelius, B., Bjorck, 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., Hamsten, A., IMPROVE Study Grp, Medicum, Department of Psychology and Logopedics, University of Helsinki, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Developmental Psychology Research Group, Luan, Jian'an [0000-0003-3137-6337], Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository
- Subjects
Carotid Artery Diseases ,Male ,EXPRESSION ,endocrine system ,Genetic variants ,endocrine system diseases ,Quantitative Trait Loci ,PATHOPHYSIOLOGY ,DEPENDENT DIABETES-MELLITUS ,Vascular Remodeling ,Carotid Intima-Media Thickness ,Polymorphism, Single Nucleotide ,INTIMA-MEDIA THICKNESS ,Gene Frequency ,Risk Factors ,Intima-media-thickness ,Humans ,Genetic Predisposition to Disease ,CORONARY-HEART-DISEASE ,COHORT ,cardiovascular diseases ,Mendelian randomisation ,EUROPEAN POPULATION ,COMMON ,Genetic Association Studies ,Chromosomes, Human, Pair 15 ,MEN ,Single nucleotide polymorphisms ,Mendelian Randomization Analysis ,Atherosclerosis ,INSULIN ,Europe ,Phenotype ,3121 General medicine, internal medicine and other clinical medicine ,Asymptomatic Diseases ,Linear Models ,Female ,hormones, hormone substitutes, and hormone antagonists ,Proinsulin - 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. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.
- Published
- 2017