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*

*Kontaktforfatter for dette arbejde

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Resumé

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
Antal sider10
ISSN1932-6203
DOI
StatusUdgivet - 15. aug. 2019

Fingeraftryk

Medical problems
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
diabetes
Glutamate Decarboxylase
glycohemoglobin
Fasting
glutamic acid
Odds Ratio
odds ratio
glucose
gene frequency
fasting
Glucose
antibodies
Plasmas
Antibodies
Metabolism
metabolism

Citer dette

Sun, J., Have, C. T., Hollensted, M., Grarup, N., Linneberg, A., Pedersen, O., ... 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
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. / Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. I: PLOS ONE. 2019 ; Bind 14, Nr. 8.
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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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Sun, J, Have, CT, Hollensted, M, Grarup, N, Linneberg, A, Pedersen, O, Nielsen, JS, Rungby, J, Christensen, C, Brandslund, I, Kristiansen, K, Jun, W, Hansen, T & Gjesing, AP 2019, 'Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants', PLOS ONE, bind 14, nr. 8, e0220805. https://doi.org/10.1371/journal.pone.0220805

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

I: PLOS ONE, Bind 14, Nr. 8, e0220805, 15.08.2019.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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 - 2019/8/15

Y1 - 2019/8/15

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

VL - 14

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 8

M1 - e0220805

ER -

Sun J, Have CT, Hollensted M, Grarup N, Linneberg A, Pedersen O et al. Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. PLOS ONE. 2019 aug 15;14(8). e0220805. https://doi.org/10.1371/journal.pone.0220805