TY - JOUR
T1 - 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
AU - Strawbridge, Rona J.
AU - Silveira, Angela
AU - Hoed, Marcel den
AU - Gustafsson, Stefan
AU - Luan, Jian'an
AU - Rybin, Denis
AU - Dupuis, Josée
AU - Li-Gao, Ruifang
AU - Kavousi, Maryam
AU - Dehghan, Abbas
AU - Haljas, Kadri
AU - Lahti, Jari
AU - Gådin, Jesper R.
AU - Bäcklund, Alexandra
AU - de Faire, Ulf
AU - Gertow, Karl
AU - Giral, Phillipe
AU - Goel, Anuj
AU - Humphries, Steve E.
AU - Kurl, Sudhir
AU - Langenberg, Claudia
AU - Lannfelt, Lars L.
AU - Lind, Lars
AU - Lindgren, Cecilia C.M.
AU - Mannarino, Elmo
AU - Mook-Kanamori, Dennis O.
AU - Morris, Andrew P.
AU - de Mutsert, Renée
AU - Rauramaa, Rainer
AU - Saliba-Gustafsson, Peter
AU - Sennblad, Bengt
AU - Smit, Andries J.
AU - Syvänen, Ann Christine
AU - Tremoli, Elena
AU - Veglia, Fabrizio
AU - Zethelius, Björn
AU - Björck, Hanna M.
AU - Eriksson, Johan G.
AU - Hofman, Albert
AU - Franco, Oscar H.
AU - Watkins, Hugh
AU - Jukema, J. Wouter
AU - Florez, Jose C.
AU - Wareham, Nicholas J.
AU - Meigs, James B.
AU - Ingelsson, Erik
AU - Baldassarre, Damiano
AU - Hamsten, Anders
AU - the IMPROVE study group
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Genetic variants
KW - Intima-media-thickness
KW - Mendelian randomisation
KW - Proinsulin
KW - Single nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85031116559&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031116559&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2017.09.031
DO - 10.1016/j.atherosclerosis.2017.09.031
M3 - Article
AN - SCOPUS:85031116559
VL - 266
SP - 196
EP - 204
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
ER -