| Title: | Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 26 May 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37235780/ |
| DOI: | https://doi.org/10.1210/clinem/dgad290 |
| URL: | https://academic.oup.com/jcem/advance-article-pdf/doi/10.1210/clinem/dgad290/50625953/dgad290.pdf |
Publication 11495
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Abstract
CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology.</p>
OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations.</p>
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.</p>
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 A1c.</p>
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.</p>
18 Authors
- Josefine U Melchiorsen
- Kimmie V Sørensen
- Jette Bork-Jensen
- Hüsün S Kizilkaya
- Lærke S Gasbjerg
- Alexander S Hauser
- Jørgen Rungby
- Henrik T Sørensen
- Allan Vaag
- Jens S Nielsen
- Oluf Pedersen
- Allan Linneberg
- Bolette Hartmann
- Anette P Gjesing
- Jens J Holst
- Torben Hansen
- Mette M Rosenkilde
- Niels Grarup
Enabling scientific discoveries that improve human health