14-fold increased prevalence of rare glucokinase gene variant carriers in unselected Danish patients with newly diagnosed type 2 diabetes
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Rare variants in the glucokinase gene (GCK) cause Maturity-Onset Diabetes of the Young (MODY2/GCK-MODY). We investigated the prevalence of GCK variants, phenotypic characteristics, micro- and macrovascular disease at baseline and follow-up, and treatment among individuals with and without pathogenic GCK variants.
Methods
This is a cross-sectional study in a population-based cohort of 5,433 individuals without diabetes (Inter99 cohort) and in 2,855 patients with a new clinical diagnosis of type 2 diabetes (DD2 cohort) with sequencing of GCK. Phenotypic characteristics, presence of micro- and macrovascular disease and treatment information were available for patients in the DD2 cohort at baseline and after an average follow-up of 7.4 years.
Results
Twenty-two carriers of potentially deleterious GCK variants were found among patients with type 2 diabetes compared to three among 5,433 nondiabetic individuals [OR = 14.1 (95 % CI 4.2; 47.0), p = 8.9*10-6]. Patients with type 2 diabetes carrying GCK variants had significantly lower waist circumference, hip circumference and BMI, compared to non-carriers. Three GCK variant carriers with diabetes had microvascular complications during follow-up.
Conclusions
Approximately 0.8% of Danish patients with newly diagnosed type 2 diabetes carry non-synonymous variants in GCK and resemble patients with GCK-MODY. Glucose-lowering treatment cessation should be considered in this subset of diabetes patients.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 110159 |
| Tidsskrift | Diabetes Research and Clinical Practice |
| Vol/bind | 194 |
| Antal sider | 9 |
| ISSN | 0168-8227 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
The study was partially performed at the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation, Denmark (www.metabol.ku.dk). The study was also supported by the Novo Nordisk Foundation, Denmark through the Challenge Program (NNF18OC0033950) and the Steno Collaborative Grants (NNF17OC0028328). The study also received funding from Innovation Fund Denmark (number 9090-00078B). Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Funding Information:
The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison purposes. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. From Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark, we wish to thank A. Forman, T. H. Lorentzen and G. J. Klavsen for laboratory assistance, P. Sandbeck for data management, and C. Verdich and L. Ryborg for grant management. The guarantor of the current study is Professor Torben Hansen. Authors have no relevant conflicts of interest to disclose. AL, JSN, HTS, IV, HBN, AV, JR, OP and TH were responsible for conception. APG, CTH, LE, and TH were responsible for design of the study. AL, JSN, HTS, IV, HBN, AV and JR were responsible for sample collection. APG, CTH, LE, ACBT, MH, NG, LBC, RWT and TH took part in the analyses. APG, OP, NG and TH were involved in funding acquisition. APG and TH drafted the article. APG, CTH, LE, ACBT, MH, NG, LBC, RWT, JSN, HTS, AV, OP and TH critically revised the manuscript and contributed to the discussion. The final version of the paper was read and approved by all authors. The study was partially performed at the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation, Denmark (www.metabol.ku.dk). The study was also supported by the Novo Nordisk Foundation, Denmark through the Challenge Program (NNF18OC0033950) and the Steno Collaborative Grants (NNF17OC0028328). The study also received funding from Innovation Fund Denmark (number 9090-00078B). Funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2022 The Author(s)
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