Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 108, No. 11, 2023, p. 2821–2833.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Melchiorsen, JU, Sørensen, KV, Bork-Jensen, J, Kizilkaya, HS, Gasbjerg, LS, Hauser, AS, Rungby, J, Sørensen, HT, Vaag, A, Nielsen, JS, Pedersen, O, Linneberg, A, Hartmann, B, Gjesing, AP, Holst, JJ, Hansen, T, Rosenkilde, MM & Grarup, N 2023, 'Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes', Journal of Clinical Endocrinology and Metabolism, vol. 108, no. 11, pp. 2821–2833. https://doi.org/10.1210/clinem/dgad290

APA

Melchiorsen, J. U., Sørensen, K. V., Bork-Jensen, J., Kizilkaya, H. S., Gasbjerg, L. S., Hauser, A. S., Rungby, J., Sørensen, H. T., Vaag, A., Nielsen, J. S., Pedersen, O., Linneberg, A., Hartmann, B., Gjesing, A. P., Holst, J. J., Hansen, T., Rosenkilde, M. M., & Grarup, N. (2023). Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes. Journal of Clinical Endocrinology and Metabolism, 108(11), 2821–2833. https://doi.org/10.1210/clinem/dgad290

Vancouver

Melchiorsen JU, Sørensen KV, Bork-Jensen J, Kizilkaya HS, Gasbjerg LS, Hauser AS et al. Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes. Journal of Clinical Endocrinology and Metabolism. 2023;108(11):2821–2833. https://doi.org/10.1210/clinem/dgad290

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. / Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes. In: Journal of Clinical Endocrinology and Metabolism. 2023 ; Vol. 108, No. 11. pp. 2821–2833.

Bibtex

@article{a4be0150c3b94eeea26f7d3001f01615,
title = "Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes",
abstract = "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.",
author = "Melchiorsen, {Josefine U} and S{\o}rensen, {Kimmie V} and Jette Bork-Jensen and Kizilkaya, {H{\"u}s{\"u}n S} and Gasbjerg, {L{\ae}rke S} and Hauser, {Alexander S} and J{\o}rgen Rungby and S{\o}rensen, {Henrik T.} and Allan Vaag and Nielsen, {Jens S.} and Oluf Pedersen and Allan Linneberg and Bolette Hartmann and Gjesing, {Anette P} and Holst, {Jens J} and Torben Hansen and Rosenkilde, {Mette M} and Niels Grarup",
note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.",
year = "2023",
doi = "10.1210/clinem/dgad290",
language = "English",
volume = "108",
pages = "2821–2833",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "Oxford University Press",
number = "11",

}

RIS

TY - JOUR

T1 - Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes

AU - Melchiorsen, Josefine U

AU - Sørensen, Kimmie V

AU - Bork-Jensen, Jette

AU - Kizilkaya, Hüsün S

AU - Gasbjerg, Lærke S

AU - Hauser, Alexander S

AU - Rungby, Jørgen

AU - Sørensen, Henrik T.

AU - Vaag, Allan

AU - Nielsen, Jens S.

AU - Pedersen, Oluf

AU - Linneberg, Allan

AU - Hartmann, Bolette

AU - Gjesing, Anette P

AU - Holst, Jens J

AU - Hansen, Torben

AU - Rosenkilde, Mette M

AU - Grarup, Niels

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1210/clinem/dgad290

DO - 10.1210/clinem/dgad290

M3 - Journal article

C2 - 37235780

VL - 108

SP - 2821

EP - 2833

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 11

ER -

ID: 350988852