Rare heterozygous loss-of-function variants in the human GLP-1 receptor do not associate with cardiometabolic phenotypes
| العنوان: | Rare heterozygous loss-of-function variants in the human GLP-1 receptor do not associate with cardiometabolic phenotypes |
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| المؤلفون: | 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 |
| المصدر: | The Journal of Clinical Endocrinology & Metabolism. |
| بيانات النشر: | The Endocrine Society, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Endocrinology, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Biochemistry |
| الوصف: | Context Impact of lost GLP-1 receptor function in human physiology. Objective Identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. Methods We sequenced GLP1R in 8,642 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 cAMP formation and beta-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signalling (LoS) variants and cardiometabolic phenotypes in 2,930 patients with type 2 diabetes and 5,712 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 Caucasian 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 signalling compared to wildtype. 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 HbA1c. Conclusion Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as non-carriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants. |
| تدمد: | 1945-7197 0021-972X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_________::f42765a2459edd5eb09d9dd7deb86cd2Test https://doi.org/10.1210/clinem/dgad290Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi...........f42765a2459edd5eb09d9dd7deb86cd2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457197 0021972X |
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