Abstract
BackgroundBased 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.MethodsWe 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.ResultsIn 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).ConclusionRare 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.
Highlights
GLIS3 is encoding a member of the Kruppel-like zinc finger protein subfamily GLI-similar 3 which is a transcription factor playing a critical role both as a repressor and activator of transcription [1]
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)
A significantly increased HbA1c was found among patients with type 2 diabetes and with GADApositive diabetes carrying rare GLIS3 variants compared to non-carriers of rare GLIS3 variants with diabetes (p = 0.02 and p = 0.004, respectively)
Summary
GLIS3 is encoding a member of the Kruppel-like zinc finger protein subfamily GLI-similar 3 which is a transcription factor playing a critical role both as a repressor and activator of transcription [1]. The transcriptional regulation by GLIS3 is mediated through an interaction between GLIS-binding sites (GLISBS) in the regulatory region of target genes and zinc finger domains in GLIS3 [1, 4]. Glis deficient mice have a decreased beta-cell mass and develop neonatal diabetes in addition to hypothyroidism, and cystic kidney disease [5]. Glis missense variants identified in Goto-Kakizaki rats have been found to increase basal production of insulin but reduce the glucose stimulated insulin secretion in INS1-cells [6]. 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
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