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
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 atheros...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2017
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| _version_ | 1797073885224501248 |
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| author | 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, AC 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 |
| author_facet | 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, AC 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 |
| author_sort | Strawbridge, RJ |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T23:28:22Z |
| format | Journal article |
| id | oxford-uuid:6b30bc30-f892-48e9-bbd3-ec70eee0ade3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:28:22Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:6b30bc30-f892-48e9-bbd3-ec70eee0ade32022-03-26T19:02:20ZIdentification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisationJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6b30bc30-f892-48e9-bbd3-ec70eee0ade3EnglishSymplectic Elements at OxfordElsevier2017Strawbridge, RJSilveira, AHoed, MDGustafsson, SLuan, JRybin, DDupuis, JLi-Gao, RKavousi, MDehghan, AHaljas, KLahti, JGådin, JRBäcklund, Ade Faire, UGertow, KGiral, PGoel, AHumphries, SEKurl, SLangenberg, CLannfelt, LLLind, LLindgren, CCMMannarino, EMook-Kanamori, DOMorris, APde Mutsert, RRauramaa, RSaliba-Gustafsson, PSennblad, BSmit, AJSyvänen, ACTremoli, EVeglia, FZethelius, BBjörck, HMEriksson, JGHofman, AFranco, OHWatkins, HJukema, JWFlorez, JCWareham, NJMeigs, JBIngelsson, EBaldassarre, DHamsten, AIncreased 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. |
| spellingShingle | 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, AC 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 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 |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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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