Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes
Authors' 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.
Study context
- Population
- Danish individuals with T2D or normal glucose tolerance (2930 patients with T2D, 5712 population-based cohort); 330,566 unrelated White exome-sequenced UK Biobank participantsDanish
- Participants
- 8,642 individuals
- Exposure
- Carriers of GLP1R loss-of-signaling (LoS) or predicted loss-of-function (pLoF) variants vs noncarriers
- Outcome
- Nonsynonymous GLP1R variants and LoS variants vs T2D
Methodological detailscross-sectional, exome sequencing, UK Biobank replication
- Cross-sectional
- Exome sequencing
- UK Biobank replication
Main finding
As reported in the abstract
Nonsynonymous variants identified in GLP1R
36
Variants with significant loss in GLP-1-induced cyclic adenosine monophosphate (cAMP) signaling vs wild-type
10
Observational data: associations, not effects.
Further findings
pLoF GLP1R variants (UK Biobank) and cardiometabolic phenotypes
- pLoF GLP1R variants studied
- 60
- No substantial cardiometabolic associations, despite a small effect on HbA1c
Original publication
Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes. J Clin Endocrinol Metab. Published 26 May 2023. doi:10.
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