Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants

PLoS One. 2019 Aug 15;14(8):e0220805. doi: 10.1371/journal.pone.0220805. eCollection 2019.

Abstract

Background: Based on the association of common GLIS3 variants with various forms of diabetes and the biological role of GLIS3 in beta-cells, we sequenced GLIS3 in non-diabetic and diabetic Danes to investigate the effect of rare missense variants on glucose metabolism.

Methods: We sequenced 53 patients with maturity-onset diabetes of the young (MODY), 5,726 non-diabetic participants, 2,930 patients with newly diagnosed type 2 diabetes and 206 patients with glutamic acid decarboxylase antibody (GADA) -positive diabetes.

Results: In total we identified 86 rare (minor allele frequency < 0.1%) missense variants. None was considered causal for the presence of MODY. Among patients with type 2 diabetes, we observed a higher prevalence of rare GLIS3 missense variants (2.5%) compared to non-diabetic individuals (1.8%) (odds ratio of 1.37 (interquartile range:1.01-1.88, p = 0.04)). A significantly increased HbA1c was found among patients with type 2 diabetes and with GADA-positive diabetes carrying rare GLIS3 variants compared to non-carriers of rare GLIS3 variants with diabetes (p = 0.02 and p = 0.004, respectively). One variant (p.I28V) was found to have a minor allele frequency of only 0.03% among patients with type 2 diabetes compared to 0.2% among non-diabetic individuals suggesting a protective function (odds ratio of 0.20 (interquartile range: 0.005-1.4, p = 0.1)), an effect which was supported by publically available data. This variant was also associated with a lower level of fasting plasma glucose among non-diabetic individuals (p = 0.046).

Conclusion: Rare missense variants in GLIS3 associates nominally with increased level of HbA1c and increased risk of developing type 2 diabetes. In contrast, the rare p.I28V variant associate with reduced level of fasting plasma glucose and may be protective against type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Blood Glucose
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Prediabetic State / blood
  • Prediabetic State / genetics*
  • Repressor Proteins / genetics*
  • Trans-Activators / genetics*

Substances

  • Blood Glucose
  • DNA-Binding Proteins
  • GLIS3 protein, human
  • Repressor Proteins
  • Trans-Activators

Supplementary concepts

  • Mason-Type Diabetes

Grants and funding

This project received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667191 (authors awarded: APG, NG and TH). In addition, the study was supported from the Danish Diabetes Academy, the Danish Medical Research Council, the European Foundation for the Study of Diabetes (EFSD), the Novo Nordisk Foundation (Immunometabolism, NNF15CC0018486) and the Danish Diabetes Association. The DD2 cohort was funded by the Danish Agency for Science (grant no. 09-067009 and 09-075724) (authors awarded: JSN and JR). 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 (www.metabol.ku.dk). The BGI provided support in the form of salaries for author [JS and KK], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. The iCarbonX provided support in the form of salaries for author [WJ], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No other funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.