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

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

doi:10.1371/journal.pone.0220805

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

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^*

^*Corresponding author for this work

2 Citations (Scopus)

11 Downloads (Pure)

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.

Original language	English
Article number	e0220805
Journal	PLoS ONE
Volume	14
Issue number	8
Number of pages	10
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0220805
Publication status	Published - 1 Aug 2019

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Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variantsFinal published version, 494 KBLicence: CC BY

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Sun, J., Have, C. T., Hollensted, M., Grarup, N., Linneberg, A., Pedersen, O., Nielsen, J. S., Rungby, J., Christensen, C., Brandslund, I., Kristiansen, K., Jun, W., Hansen, T., & Gjesing, A. P. (2019). Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. PLoS ONE, 14(8), [e0220805]. https://doi.org/10.1371/journal.pone.0220805

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title = "Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants",

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.",

author = "Jihua Sun and Have, {Christian Theil} and Mette Hollensted and Niels Grarup and Allan Linneberg and Oluf Pedersen and Nielsen, {Jens Steen} and J{\o}rgen Rungby and Cramer Christensen and Ivan Brandslund and Karsten Kristiansen and Wang Jun and Torben Hansen and Gjesing, {Anette P.}",

year = "2019",

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day = "1",

doi = "10.1371/journal.pone.0220805",

language = "English",

volume = "14",

journal = "PLoS Computational Biology",

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T1 - Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants

AU - Sun, Jihua

AU - Have, Christian Theil

AU - Hollensted, Mette

AU - Grarup, Niels

AU - Linneberg, Allan

AU - Pedersen, Oluf

AU - Nielsen, Jens Steen

AU - Rungby, Jørgen

AU - Christensen, Cramer

AU - Brandslund, Ivan

AU - Kristiansen, Karsten

AU - Jun, Wang

AU - Hansen, Torben

AU - Gjesing, Anette P.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0220805

DO - 10.1371/journal.pone.0220805

M3 - Journal article

C2 - 31415576

AN - SCOPUS:85070679367

SN - 1932-6203

VL - 14

JO - PLoS Computational Biology

JF - PLoS Computational Biology

IS - 8

M1 - e0220805

ER -

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

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