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 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 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. β-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 β-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 β-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 β-cell antigens.

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes: Phase and Endotype Specific Effects

“…A meta-analysis of the significance of STAT4 rs7574865 T1D risk allele T has confirmed its association with T1D in multiple populations, in addition to the already earlier found association with other autoimmune diseases ( 34 ). A recent study also reported a higher STAT4 expression level in peripheral blood mononuclear cells in T1D cases compared to controls and an association of the rs7574865 T allele with younger age at the T1D diagnosis ( 35 ). The finding of a young age at diagnosis in risk allele positive children concurs with our finding of rs7574865 risk allele T increasing development of AABs and with the association of IAA as the first AAB because IAA dominates over GADA as the first AAB among the youngest seroconverted children, which is also reflected in a younger age at diagnosis ( 36 ).…”

Assessing the association of rs7574865 STAT4 gene variant and type 1 diabetes mellitus among Egyptian patients

“…Most of the earlier studies on Asian and European populations confirmed that rs7574865 has a role in the incidence of diabetes type 1 [43,44]. Also, a meta-analysis study performed on Caucasians and Asian subjects showed that it was associated with diabetes risk (P < 0.5) [45], and there was a study that confirmed the STAT4 was overexpressed from T1D Polish patients [46]. In contrast, a study among the Korean population, the Tunisian and Brazilian population showed no evidence of the association of the variant and T1D [20,47,48], while our study showed that the rs7574865 (T) allele is accompanied with increased risk for type 1 diabetes among Egyptians, same as another study on Greek patients [49] and Northeastern Chinese Han population [41,44].…”

Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

“…In this investigation, we also constructed a miRNA-hub gene regulatory network and TF-hub gene regulatory network for the hub genes. Mirza et al [275], Warshauer et al [276], Fichna et al [277], Zhang et al [278] and Abd-Allah et al [279] reported that the altered expression of the hsa-mir-133a-3p, STAT3, STAT4, SOX2 and VDR (vitamin D receptor) are correlated with T1DM. Recent studies have proposed that the hsa-mir-133a-3p [280], STAT3 [281], STAT4 [282], FOXA2 [283], FOXM1 [284], EGR1 [285], CUX1 [286] and VDR (vitamin D receptor) [287] are associated with obesity.…”