Karhunen, V; Daghlas, I; Zuber, V; Vujkovic, M; Olsen, AK; Knudsen, LB; Haynes, WG; Howson, JMM; Gill, D
(2021)
Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling.
Diabetologia, 64 (12).
pp. 2773-2778.
ISSN 1432-0428
https://doi.org/10.1007/s00125-021-05564-7
SGUL Authors: Gill, Dipender Preet Singh
Abstract
AIMS/HYPOTHESIS: The aim of this study was to leverage human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide (GIP) signalling. METHODS: Data were obtained from summary statistics of large-scale genome-wide association studies. We examined whether genetic associations for type 2 diabetes liability in the GIP and GIPR genes co-localised with genetic associations for 11 cardiometabolic outcomes. For those outcomes that showed evidence of co-localisation (posterior probability >0.8), we performed Mendelian randomisation analyses to estimate the association of genetically proxied GIP signalling with risk of cardiometabolic outcomes, and to test whether this exceeded the estimate observed when considering type 2 diabetes liability variants from other regions of the genome. RESULTS: Evidence of co-localisation with genetic associations of type 2 diabetes liability at both the GIP and GIPR genes was observed for five outcomes. Mendelian randomisation analyses provided evidence for associations of lower genetically proxied type 2 diabetes liability at the GIP and GIPR genes with lower BMI (estimate in SD units -0.16, 95% CI -0.30, -0.02), C-reactive protein (-0.13, 95% CI -0.19, -0.08) and triacylglycerol levels (-0.17, 95% CI -0.22, -0.12), and higher HDL-cholesterol levels (0.19, 95% CI 0.14, 0.25). For all of these outcomes, the estimates were greater in magnitude than those observed when considering type 2 diabetes liability variants from other regions of the genome. CONCLUSIONS/INTERPRETATION: This study provides genetic evidence to support a beneficial role of sustained GIP signalling on cardiometabolic health greater than that expected from improved glycaemic control alone. Further clinical investigation is warranted. DATA AVAILABILITY: All data used in this study are publicly available. The scripts for the analysis are available at: https://github.com/vkarhune/GeneticallyProxiedGIP .
Item Type: |
Article
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Additional Information: |
© The Author(s) 2021
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: |
Cardiometabolic disease, Co-localisation, Glucose-dependent insulinotropic polypeptide, Mendelian randomisation, Type 2 diabetes mellitus, Cardiometabolic disease, Co-localisation, Glucose-dependent insulinotropic polypeptide, Mendelian randomisation, Type 2 diabetes mellitus, Endocrinology & Metabolism, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, 1117 Public Health and Health Services |
SGUL Research Institute / Research Centre: |
Academic Structure > Infection and Immunity Research Institute (INII) |
Journal or Publication Title: |
Diabetologia |
ISSN: |
1432-0428 |
Language: |
eng |
Dates: |
Date | Event |
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December 2021 | Published | 9 September 2021 | Published Online | 22 July 2021 | Accepted |
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Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
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PubMed ID: |
34505161 |
Web of Science ID: |
WOS:000694591500001 |
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Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113690 |
Publisher's version: |
https://doi.org/10.1007/s00125-021-05564-7 |
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