STAT4 Sequence Variant and Elevated Gene Expression Are Associated with Type 1 Diabetes in Polish Children

Introduction: Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells, resulting from coincident genetic predisposition and some environmental triggers. Signal transducer and activator of transcription 4 (STAT 4) gene encodes a transcription factor, which promotes Th1 cell differentiation, interferon. production, and development of Th17 cells. Polymorphisms of STAT 4 are associated with several autoimmune conditions, while studies in T1D provided inconsistent results. This analysis was designed to investigate the association of STAT 4 rs7574865 with T1D in Polish children and to assess STAT 4 expression in newly diagnosed subjects. Material and methods: Rs7574865 was genotyped in 656 T1D children and 782 healthy individuals. STAT 4 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 29 children with T1D and 27 age-matched controls. beta-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 beta-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). STAT 4 was overexpressed in PBMCs from T1D patients (p = 0.008), especially subjects with two/three circulating beta-cell antibodies (p < 0.001). Conclusions: The study confirms an association of STAT 4 rs7574865 with T1D in Polish patients, and provides an evidence for its relationship with an earlier disease onset and concomitant thyroid autoimmunity. STAT 4 expression appears elevated in T1D, especially with more severe reaction against beta-cell antigens.