Dataset Information

STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

ABSTRACT: Introduction:Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic ? cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon ? production, and development of Th17 cells. Polymorphisms of STAT4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent results. This analysis was designed to investigate the association of STAT4 rs7574865 with T1D in Polish children and to assess STAT4 expression in newly diagnosed subjects. Material and methods:Rs7574865 was genotyped in 656 T1D children and 782 healthy individuals. STAT4 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 29 children with T1D and 27 age-matched controls. ?-cell and thyroid-specific serum autoantibodies were assessed with radioimmunoassays. Results:The distribution of rs7574865 genotypes and alleles demonstrated significant difference (p = 0.002, p < 0.001, respectively) between patients vs. controls. Carriers of the minor T allele presented earlier T1D onset (p = 0.017). No differences were found in ?-cell autoantibody in genotype-stratified patients (p > 0.050), while anti-thyroid antibodies were more frequent in carriers of the minor allele(p = 0.039 for anti-thyroperoxidase, p = 0.007 for anti-thyroglobulin antibodies, respectively). STAT4 was overexpressed in PBMCs from T1D patients (p = 0.008), especially subjects with two/three circulating ?-cell antibodies (p < 0.001). Conclusions:The study confirms an association of STAT4 rs7574865 with T1D in Polish patients, and provides an evidence for its relationship with an earlier disease onset and concomitant thyroid autoimmunity. STAT4 expression appears elevated in T1D, especially with more severe reaction against ?-cell antigens.

SUBMITTER: Fichna M

PROVIDER: S-EPMC7226553 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>STAT4</i> sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

Fichna Marta M Żurawek Magdalena M Bogusz-Górna Klaudia K Małecki Piotr P PP Niechciał Elżbieta E Sidoruk Anna A Furman Katarzyna K Fichna Piotr P

Central-European journal of immunology 20200101 1

<h4>Introduction</h4>Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic β cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon γ production, and development of Th17 cells. Polymorphisms of STAT4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent re ...[more]

PMID: 32425676

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Project description:Type 1 diabetes (T1D) is an autoimmune disease that is typically diagnosed in children. The aim of the present study was to identify potential genes involved in the pathogenesis of childhood T1D. Two datasets of mRNA expression in children with T1D were obtained from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) in children with T1D were identified. Functional analysis was performed and a protein‑protein interaction (PPI) network was constructed, as was a transcription factor (TF)‑target network. The expression of selected DEGs was further assessed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. Electronic validation and diagnostic value analysis of the identified DEGs [cytokine inducible SH2 containing protein (CISH), SR‑related CTD associated factor 11 (SCAF11), estrogen receptor 1 (ESR1), Rho GTPase activating protein 25 (ARHGAP25), major histocompatibility complex, class II, DR β4 (HLA‑DRB4) and interleukin 23 subunit α (IL23A)] was performed in the GEO dataset. Compared with the normal control group, a total of 1,467 DEGs with P<0.05 were identified in children with T1D. CISH and SCAF11 were determined to be the most up‑ and downregulated genes, respectively. Heterogeneous nuclear ribonucleoprotein D (HNRNPD; degree=33), protein kinase AMP‑activated catalytic subunit α1 (PRKAA1; degree=11), integrin subunit α4 (ITGA4; degree=8) and ESR1 (degree=8) were identified in the PPI network as high‑degree genes. ARHGAP25 (degree=12), HNRNPD (degree=10), HLA‑DRB4 (degree=10) and IL23A (degree=9) were high‑degree genes identified in the TF‑target network. RT‑qPCR revealed that the expression of HNRNPD, PRKAA1, ITGA4 and transporter 2, ATP binding cassette subfamily B member was consistent with the results of the integrated analysis. Furthermore, the results of the electronic validation were consistent with the bioinformatics analysis. SCAF11, CISH and ARHGAP25 were identified to possess value as potential diagnostic markers for children with T1D. In conclusion, identifying DEGs in children with T1D may contribute to our understanding of its pathogenesis, and such DEGs may be used as diagnostic biomarkers for children with T1D.

Dataset Information

STAT4 sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

Publications

<i>STAT4</i> sequence variant and elevated gene expression are associated with type 1 diabetes in Polish children.

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