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Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus

BACKGROUND: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomiz...

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Autores principales: Wang, Wenyi, Tesfay, Ephrem Baraki, van Klinken, Jan Bert, Willems van Dijk, Ko, Bartke, Andrzej, van Heemst, Diana, Noordam, Raymond
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749721/
https://www.ncbi.nlm.nih.gov/pubmed/35656699
http://dx.doi.org/10.1093/ije/dyac119
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author Wang, Wenyi
Tesfay, Ephrem Baraki
van Klinken, Jan Bert
Willems van Dijk, Ko
Bartke, Andrzej
van Heemst, Diana
Noordam, Raymond
author_facet Wang, Wenyi
Tesfay, Ephrem Baraki
van Klinken, Jan Bert
Willems van Dijk, Ko
Bartke, Andrzej
van Heemst, Diana
Noordam, Raymond
author_sort Wang, Wenyi
collection PubMed
description BACKGROUND: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomization (MR) analyses in the UK Biobank. METHODS: We conducted Cox proportional hazard analyses in 451 232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13 247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect estimates of individual instruments (P-value for Q statistic = 4.03e−145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by over-representation analyses. RESULTS: In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes [hazard ratio (HR): 1.31; 95% CI: 1.23–1.39). In contrast, in the two-sample MR analyses, higher genetically influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth hormone signalling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity. CONCLUSIONS: The IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.
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spelling pubmed-97497212022-12-15 Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus Wang, Wenyi Tesfay, Ephrem Baraki van Klinken, Jan Bert Willems van Dijk, Ko Bartke, Andrzej van Heemst, Diana Noordam, Raymond Int J Epidemiol Diabetes BACKGROUND: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of human age-related diseases such as type 2 diabetes (T2D). Here, we investigated the association between IGF-1 and T2D using (clustered) Mendelian randomization (MR) analyses in the UK Biobank. METHODS: We conducted Cox proportional hazard analyses in 451 232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13 247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent single nucleotide polymorphisms (SNPs) associated with IGF-1. Given the heterogeneity between the MR effect estimates of individual instruments (P-value for Q statistic = 4.03e−145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by over-representation analyses. RESULTS: In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes [hazard ratio (HR): 1.31; 95% CI: 1.23–1.39). In contrast, in the two-sample MR analyses, higher genetically influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of MR effect estimates of individual instruments, six clusters of genetically determined IGF-1 associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth hormone signalling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity. CONCLUSIONS: The IGF-1-associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of MR effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes. Oxford University Press 2022-06-03 /pmc/articles/PMC9749721/ /pubmed/35656699 http://dx.doi.org/10.1093/ije/dyac119 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Diabetes
Wang, Wenyi
Tesfay, Ephrem Baraki
van Klinken, Jan Bert
Willems van Dijk, Ko
Bartke, Andrzej
van Heemst, Diana
Noordam, Raymond
Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title_full Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title_fullStr Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title_full_unstemmed Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title_short Clustered Mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
title_sort clustered mendelian randomization analyses identify distinct and opposing pathways in the association between genetically influenced insulin-like growth factor-1 and type 2 diabetes mellitus
topic Diabetes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9749721/
https://www.ncbi.nlm.nih.gov/pubmed/35656699
http://dx.doi.org/10.1093/ije/dyac119
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