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

Marta Fichna; Magdalena Żurawek; Klaudia Bogusz-Górna; Piotr P Małecki; Elżbieta Niechciał; Anna Sidoruk; Katarzyna Furman; Piotr Fichna

doi:10.5114/ceji.2019.92492

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

Cent Eur J Immunol. 2020;45(1):22-28. doi: 10.5114/ceji.2019.92492.

Authors

Marta Fichna¹, Magdalena Żurawek², Klaudia Bogusz-Górna³, Piotr P Małecki⁴, Elżbieta Niechciał³, Anna Sidoruk⁵, Katarzyna Furman⁶, Piotr Fichna³

Affiliations

¹ Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznan, Poland.
² Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
³ Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland.
⁴ Rare Diseases Medical Department, Sanofi Genzyme, Poland.
⁵ Central Laboratory of the Poznan University of Medical Sciences Pediatric Hospital, Poznan, Poland.
⁶ Ludwik Perzyna Regional Hospital, Kalisz, Poland.

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 γ-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.

Keywords: STAT4; autoantibody; autoimmunity; polymorphism; type 1 diabetes.