Sequencing reveals protective and pathogenic effects on development of diabetes of rare GLIS3 variants
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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.
In: PLoS ONE, Vol. 14, No. 8, e0220805, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2019
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
VL - 14
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 8
M1 - e0220805
ER -
ID: 227043384