Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants.
<h4>Background</h4>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.<h4>Me...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0220805 |
| _version_ | 1818726501976113152 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jihua Sun |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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. |
| first_indexed | 2024-12-17T21:59:13Z |
| format | Article |
| id | doaj.art-57a6bf9899b3414e87b059fe8ae3f9af |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T21:59:13Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-57a6bf9899b3414e87b059fe8ae3f9af2022-12-21T21:31:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01148e022080510.1371/journal.pone.0220805Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants.Jihua SunChristian Theil HaveMette HollenstedNiels GrarupAllan LinnebergOluf PedersenJens Steen NielsenJørgen RungbyCramer ChristensenIvan BrandslundKarsten KristiansenWang JunTorben HansenAnette P Gjesing<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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).<h4>Conclusion</h4>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.https://doi.org/10.1371/journal.pone.0220805 |
| spellingShingle | 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 Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. PLoS ONE |
| title | Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. |
| title_full | Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. |
| title_fullStr | Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. |
| title_full_unstemmed | Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. |
| title_short | Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants. |
| title_sort | sequencing reveals protective and pathogenic effects on development of diabetes of rare glis3 variants |
| url | https://doi.org/10.1371/journal.pone.0220805 |
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