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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Strawbridge , R J , Silveira , A , den Hoed , M , Gustafsson , S , Luan , J , Rybin , D , Dupuis , J , Li-Gao , R , Kavousi , M , Dehghan , A , Haljas , K , Lahti , J , Gadin , J R , Backlund , A , de Faire , U , 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 , de Mutsert , R , 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 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 , vol. 266 , pp. 196-204 . https://doi.org/10.1016/j.atherosclerosis.2017.09.031

Title: 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: Strawbridge, Rona J.; Silveira, Angela; den Hoed, Marcel; Gustafsson, Stefan; Luan, Jian'an; Rybin, Denis; Dupuis, Josee; Li-Gao, Ruifang; Kavousi, Maryam; Dehghan, Abbas; Haljas, Kadri; Lahti, Jari; Gadin, Jesper R.; Backlund, Alexandra; de Faire, Ulf; Gertow, Karl; Giral, Phillipe; Goel, Anuj; Humphries, Steve E.; Kurl, Sudhir; Langenberg, Claudia; Lannfelt, Lars L.; Lind, Lars; Lindgren, Cecilia C. M.; Mannarino, Elmo; Mook-Kanamori, Dennis O.; Morris, Andrew P.; de Mutsert, Renee; Rauramaa, Rainer; Saliba-Gustafsson, Peter; Sennblad, Bengt; Smit, Andries J.; Syvanen, Ann-Christine; Tremoli, Elena; Veglia, Fabrizio; Zethelius, Bjorn; Bjorck, Hanna M.; Eriksson, Johan G.; Hofman, Albert; Franco, Oscar H.; Watkins, Hugh; Jukema, J. Wouter; Florez, Jose C.; Wareham, Nicholas J.; Meigs, James B.; Ingelsson, Erik; Baldassarre, Damiano; Hamsten, Anders; IMPROVE Study Grp
Other contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Clinicum






Date: 2017-11
Language: eng
Number of pages: 9
Belongs to series: Atherosclerosis
ISSN: 0021-9150
DOI: https://doi.org/10.1016/j.atherosclerosis.2017.09.031
URI: http://hdl.handle.net/10138/228650
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.
Subject: Proinsulin
Atherosclerosis
Intima-media-thickness
Single nucleotide polymorphisms
Genetic variants
Mendelian randomisation
INTIMA-MEDIA THICKNESS
CORONARY-HEART-DISEASE
DEPENDENT DIABETES-MELLITUS
EUROPEAN POPULATION
COMMON
MEN
INSULIN
COHORT
PATHOPHYSIOLOGY
EXPRESSION
3121 General medicine, internal medicine and other clinical medicine
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