Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test

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  • Anna Jonsson, Københavns Universitet
  • ,
  • Sara E. Stinson, Københavns Universitet
  • ,
  • Signe S. Torekov, Københavns Universitet
  • ,
  • Tine D. Clausen, Københavns Universitet
  • ,
  • Kristine Færch, Novo Nordisk A/S, Steno Diabetes Center, Copenhagen
  • ,
  • Louise Kelstrup, Københavns Universitet
  • ,
  • Niels Grarup, Københavns Universitet
  • ,
  • Elisabeth R. Mathiesen, Københavns Universitet, Danish Diabetes Academy
  • ,
  • Peter Damm, Københavns Universitet
  • ,
  • Daniel R. Witte
  • Marit E. Jørgensen, Syddansk Universitet, Steno Diabetes Center, Copenhagen
  • ,
  • Oluf Pedersen, Københavns Universitet
  • ,
  • Jens Juul Holst, Københavns Universitet
  • ,
  • Torben Hansen, Københavns Universitet

Background: In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. Methods: Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. Results: A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10–4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta − 0.210, SE 0.037, P = 1.9 × 10–8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10–5). Conclusions: A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.

OriginalsprogEngelsk
Artikelnummer3
TidsskriftBMC Medical Genomics
Vol/bind14
ISSN1755-8794
DOI
StatusUdgivet - jan. 2021

Bibliografisk note

Funding Information:
The ADDITION-Denmark study was supported by the National Health Services in the counties of Copenhagen, Aarhus, Ringkøbing, Ribe, and Southern Jutland in Denmark; the Danish Council for Strategic Research; the Danish Research Foundation for General Practice; Novo Nordisk Foundation; the Danish Centre for Evaluation and Health Technology Assessment; the Diabetes Fund of the National Board of Health; the Danish Medical Research Council; and the Aarhus University Research Foundation. The ADDITION-PRO study was funded by an unrestricted grant from the European Foundation for the Study of Diabetes/Pfizer for Research into Cardiovascular Disease Risk Reduction in Patients with Diabetes (74550801), by the Danish Council for Strategic Research and by internal research and equipment funds from Steno Diabetes Center. The RigCoh-study was supported by The Lundbeck Foundation, Civilingeniør H. C. Bechgaard's Foundation, The Danish Diabetes Association, The Danish Medical Research Council, the Gangsted Foundation, A. P. Moeller og Hustru Chastine Mc-Kinney Moeller's Foundation, Aase og Ejner Danielsen's Foundation, The Augustinus Foundation, and The Research Foundation of Rigshospitalet. This work was supported by an unrestricted grant from the European Foundation for the Study of Diabetes/Pfizer for Research into Cardiovascular Disease Risk Reduction in Patients with Diabetes (74550801), the Danish Council for Strategic Research, the European Union’s Horizon 2020 research and Innovation programme (Grant Agreement No 667191) and internal research and equipment funds from Steno Diabetes Center. AJ is supported by the Danish Council for Independent Research, European Union, FP7, Marie Curie Actions, IEF, Lundbeck Foundation, Novo Nordisk Foundation and Danish Diabetes Academy (NNF17SA0031406). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

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