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

Authors :
Sun, Jihua
Have, Christian Theil
Hollensted, Mette
Grarup, Niels
Linneberg, Allan
Pedersen, Oluf
Nielsen, Jens Steen
Rungby, Jørgen
Christensen, Cramer
Brandslund, Ivan
Kristiansen, Karsten
Jun, Wang
Hansen, Torben
Gjesing, Anette P.
Source :
PLoS ONE. 8/14/2019, Vol. 14 Issue 8, p1-10. 10p.
Publication Year :
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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19326203
Volume :
14
Issue :
8
Database :
Academic Search Index
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
138065191
Full Text :
https://doi.org/10.1371/journal.pone.0220805