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

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  • Jihua Sun
  • Christian Theil Have
  • Mette Hollensted
  • Niels Grarup
  • Allan Linneberg
  • Oluf Pedersen
  • Jens Steen Nielsen
  • Jørgen Rungby
  • Cramer Christensen
  • Ivan Brandslund
  • Karsten Kristiansen
  • Wang Jun
  • Torben Hansen
  • Anette P Gjesing
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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.

OriginalsprogEngelsk
Artikelnummere0220805
TidsskriftPLoS One
Vol/bind14
Udgave nummer8
Sider (fra-til)e0220805
ISSN1932-6203
DOI
StatusUdgivet - 2019

ID: 57798487