Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.
J Clin Endocrinol Metab
; 108(11): 2821-2833, 2023 10 18.
Article
em En
| MEDLINE
| ID: mdl-37235780
ABSTRACT
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 ß-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 A1c.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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Cardiovasculares
/
Diabetes Mellitus Tipo 2
Tipo de estudo:
Observational_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Clin Endocrinol Metab
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Dinamarca