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Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes
CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology. OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. METHODS: We sequenced GLP1R in 8642 Dani...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584003/ https://www.ncbi.nlm.nih.gov/pubmed/37235780 http://dx.doi.org/10.1210/clinem/dgad290 |
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author | Melchiorsen, Josefine U Sørensen, Kimmie V Bork-Jensen, Jette Kizilkaya, Hüsün S Gasbjerg, Lærke S Hauser, Alexander S Rungby, Jørgen Sørensen, Henrik T Vaag, Allan Nielsen, Jens S Pedersen, Oluf Linneberg, Allan Hartmann, Bolette Gjesing, Anette P Holst, Jens J Hansen, Torben Rosenkilde, Mette M Grarup, Niels |
author_facet | Melchiorsen, Josefine U Sørensen, Kimmie V Bork-Jensen, Jette Kizilkaya, Hüsün S Gasbjerg, Lærke S Hauser, Alexander S Rungby, Jørgen Sørensen, Henrik T Vaag, Allan Nielsen, Jens S Pedersen, Oluf Linneberg, Allan Hartmann, Bolette Gjesing, Anette P Holst, Jens J Hansen, Torben Rosenkilde, Mette M Grarup, Niels |
author_sort | Melchiorsen, Josefine U |
collection | PubMed |
description | CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology. OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. METHODS: We sequenced GLP1R in 8642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cyclic adenosine monophosphate (cAMP) formation and β-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330 566 unrelated White exome-sequenced participants in the UK Biobank cohort. RESULTS: We identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1–induced cAMP signaling compared to wild-type. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on glycated hemoglobin A(1c). CONCLUSION: Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants. |
format | Online Article Text |
id | pubmed-10584003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-105840032023-10-19 Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes Melchiorsen, Josefine U Sørensen, Kimmie V Bork-Jensen, Jette Kizilkaya, Hüsün S Gasbjerg, Lærke S Hauser, Alexander S Rungby, Jørgen Sørensen, Henrik T Vaag, Allan Nielsen, Jens S Pedersen, Oluf Linneberg, Allan Hartmann, Bolette Gjesing, Anette P Holst, Jens J Hansen, Torben Rosenkilde, Mette M Grarup, Niels J Clin Endocrinol Metab Clinical Research Article CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology. OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. METHODS: We sequenced GLP1R in 8642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cyclic adenosine monophosphate (cAMP) formation and β-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330 566 unrelated White exome-sequenced participants in the UK Biobank cohort. RESULTS: We identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1–induced cAMP signaling compared to wild-type. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on glycated hemoglobin A(1c). CONCLUSION: Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants. Oxford University Press 2023-05-26 /pmc/articles/PMC10584003/ /pubmed/37235780 http://dx.doi.org/10.1210/clinem/dgad290 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. 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 | Clinical Research Article Melchiorsen, Josefine U Sørensen, Kimmie V Bork-Jensen, Jette Kizilkaya, Hüsün S Gasbjerg, Lærke S Hauser, Alexander S Rungby, Jørgen Sørensen, Henrik T Vaag, Allan Nielsen, Jens S Pedersen, Oluf Linneberg, Allan Hartmann, Bolette Gjesing, Anette P Holst, Jens J Hansen, Torben Rosenkilde, Mette M Grarup, Niels Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title_full | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title_fullStr | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title_full_unstemmed | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title_short | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
title_sort | rare heterozygous loss-of-function variants in the human glp-1 receptor are not associated with cardiometabolic phenotypes |
topic | Clinical Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10584003/ https://www.ncbi.nlm.nih.gov/pubmed/37235780 http://dx.doi.org/10.1210/clinem/dgad290 |
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