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
Year: 2017
Type: article
Study design: Observational Study
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: (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.
Source: Atherosclerosis
Authors: Rona J. Strawbridge, Angela Silveira, Marcel den Hoed, Stefan Gustafsson, Jian'an Luan, Denis Rybin, Josée Dupuis, Ruifang Li-Gao, Maryam Kavousi, Abbas Dehghan, Kadri Haljas, Jari Lahti, Jesper R. Gådin, Alexandra Bäcklund, Ulf de Faire, Karl Gertow, Phillipe Giral, Anuj Goel, Steve E. Humphries, Sudhir Kurl, Claudia Langenberg, Lars L. Lannfelt, Lars Lind, Cecilia C.M. Lindgren, Elmo Mannarino, Dennis O. Mook-Kanamori, Andrew P. Morris, Renée de Mutsert, Rainer Rauramaa, Peter Saliba-Gustafsson, Bengt Sennblad, Andries J. Smit, Ann-Christine Syvänen, Elena Tremoli, Fabrizio Veglia, Björn Zethelius, Hanna M. Björck, Johan G. Eriksson, Albert Hofman, Oscar H. Franco, Hugh Watkins, J. Wouter Jukema, Jose C. Florez, Nicholas J. Wareham, James B. Meigs, Erik Ingelsson, Damiano Baldassarre, Anders Hamsten
Institutions: Karolinska Institutet, University of Glasgow, Uppsala University, Science for Life Laboratory, University of Cambridge, MRC Epidemiology Unit, Boston University, Framingham Heart Study, Leiden University Medical Center, Erasmus MC, MRC Centre for Environment and Health, Imperial College London, University of Helsinki, Folkhälsans Forskningscentrum, Karolinska University Hospital, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Centre for Human Genetics, University of Oxford, University College London, University of Eastern Finland, University of Perugia, University of Liverpool, Kuopio University Hospital, National Bioinformatics Infrastructure Sweden, University Medical Center Groningen, University of Groningen, University of Milan, Centro Cardiologico Monzino, Helsinki University Hospital, Finnish Institute for Health and Welfare, Harvard University, Netherlands Heart Institute, Broad Institute, Massachusetts General Hospital, Stanford Medicine, Stanford University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,902
Funders: American Diabetes Association, AstraZeneca, School of Medicine, Boston University, Torsten Söderbergs Stiftelse, Helsingin Yliopisto, Finska Läkaresällskapet, Wellcome Trust, Folkhälsanin Tutkimussäätiö, National Institute for Health and Care Research, British Heart Foundation, European Commission, Universiteit Leiden, ZonMw, Erasmus Universiteit Rotterdam, Academy of Finland, Hartstichting, Ministerie van Volksgezondheid, Welzijn en Sport, Erasmus Medisch Centrum, Ministero della Salute, Ministerie van Onderwijs, Cultuur en Wetenschap, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärt-Lungfonden, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Novo Nordisk, Signe ja Ane Gyllenbergin Säätiö, Stockholms Läns Landsting, Vetenskapsrådet, Emil Aaltosen Säätiö, Leids Universitair Medisch Centrum, BHF Centre of Research Excellence, Oxford, Uppsala Universitet, Diabetesförbundet, Science for Life Laboratory, Novo Nordisk Fonden, National Institutes of Health, Sixth Framework Programme, Medical Research Council, European Research Council, Seventh Framework Programme, Sixth Framework Programme, Uppsala Multidisciplinary Center for Advanced Computational Science, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, H2020 European Research Council
Awards: G1017378214, G1044594144, G1093531541, G119964413, G1394812629, G1495020029, G150102659, G1576437321, G1606511277, G1873584668, G2063900420, G2109279595, G2114638865, G2175624253, G220799409, G2359252135, G2449448643, G250621538, G2539352280, G2580106776, G2636403020, G2742998858, G2800881060, G2861369480, G2973790809, G297885364, G3038610886, G3042145041, G3165234770, G3207356259, G3383031331, G3540777072, G3560030053, G3673804865, G36937976, RENEWAL: Dissecting the molecular genetic architecture of plasma lipid traits: identifying functional changes and their use in determining coronary heart disease causality, G3761937116, G3839646794, G3873735970, G3931106482, G393177772, G4130499527, Beyond GWAS of insulin resistance: An integrated approach to translate genetic association to function, G4461659795, G4544071696, G459060772, G4613056753, G4834061917, G4965815620, G5074278315, G5446579839, G5457026379, Causal associations of circulating biomarkers with cardiovascular disease, G5702163051, G5824843607, G582688034, G5846212695, Cardiomics: Integration of -omics methods for identification of novel drug targets and clinical biomarkers for coronary heart disease, Rare Sequence Variation and Diabetes Quantitative Traits, G6086542015, Exploitation of genomic variants affecting coronary artery disease and stroke risk for therapeutic intervention, G6638055606, G6722799667, G6729440087, G6957823285, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7254856393, G738203952, G7672858748, G7704346859, G7896170168, G8009213549, G80149192, G8023042381, NIHR Senior Investigator Award, G8506930532, SUrrogate markers for vascular Micro- and Macrovascular hard endpoints for Innovative diabetes Tools, G8819635595, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000077981, G9000079831, G9000094093, G9000124674, G9000175748, G9000217923, G9000230115, G9000309734
OpenAlex ID: W2757783262