Assessing the association of rs7574865 STAT4 gene variant and type 1 diabetes mellitus among Egyptian patients.
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ABSTRACT: Background
Variants in the signal transducer and activator of transcription 4 (STAT4) gene have an important role in the incident of multiple autoimmune diseases including type 1 diabetes mellitus (T1D). It is a genetically related auto-immune disorder that resulted from T cell-mediated destruction of pancreatic cells that are in control for the production of insulin in the blood. The current study aimed to clarify the role of STAT4 (rs7574865) variant allelic and genotypic variations in the susceptibility to type 1 diabetes among Egyptians by using the real-time PCR.Results
A total of 100 patients and 100 controls were genotyped for rs7574865, and the biochemical and anthropometric parameters were measured to show that type 1 diabetic patients had significantly higher levels of HbA1c and triglycerides compared to non-diabetic individuals (P < 0.05). And genetically, the T allele and GT genotype have a significant correlation with diabetes type 1.Conclusion
It was confirmed by this study that the rs7574865 T allele and GT genotype have a significant correlation with diabetes type 1 incidence among Egyptian patients.
SUBMITTER: Abdelmajed SS
PROVIDER: S-EPMC8333174 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNa+/K+ ATPase enzyme is essential for nerve cell membrane integrity, and reduction in its activity, probably due to ATP1A1 gene polymorphisms, is related to diabetic neuropathy progression. Therefore, the goal of the existent study is to evaluate the Na+/K+ ATPase activity in type 2 diabetes mellitus (T2DM) Egyptian patients with or without neuropathy, search for polymorphism(s) in the highly polymorphic region of ATP1A1 gene, exon 2, and study its (their) associations with T2DM with and without neuropathy.Materials and methodsA total number of 150 individuals were subclassified into healthy controls (n = 30), T2DM without complications (n = 60), and T2DM with neuropathy (n = 60).ResultsThe biochemical results exhibited a significant reduction in fasting C-Peptide and activity of Na+/K+ ATPase in T2DM patients with neuropathy followed by T2DM without complication in comparison with healthy controls. ATP1A1 exon2 was amplified by polymerase chain reaction (PCR) then digested by the PstI restriction enzyme, and the obtained data from restriction fragment length polymorphism-PCR and sequencing revealed the existence of a novel synonymous G94A single nucleotide polymorphism (SNP) at nucleotide 27 in exon 2 of ATP1A1 gene (rs1060366). Diabetic groups had only allele A, while the control group had G allele. Interestingly, individuals carrying AA genotype had a significantly lower Na+/K+ ATPase, C-peptide, and higher glycosylated hemoglobin (HBA1c %) than those having GG genotype, suggesting a possible association for this SNP, and this developed phenomenon of not only T2DM but also diabetic neuropathy.ConclusionThus, allele A of G94A SNP (rs1060366) could be a risk allele for diabetes susceptibility among Egyptian patients.
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Project description:Objectives: The signal transducer and activator of transcription 4 (STAT4) gene encodes an important transcription factor that transmits signals induced by several cytokines associated with autoimmune diseases and has been identified as a susceptibility gene for numerous autoimmune disorders. The association between STAT4 rs7574865 polymorphism and the susceptibility of autoimmune thyroid disease (AITD) has been investigated in previous case-control studies. However, the investigation results were inconsistent. Hence, a meta-analysis was performed to draw a more reliable conclusion about it. Methods: All relevant studies were searched in Embase, PubMed, Web of Science, and China National Knowledge Infrastructure, till August 20, 2018. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association. Results: A total of five independent case-control studies with 1707 AITD patients and 2316 controls were included in the present meta-analysis. The overall pooled analysis indicated that STAT4 rs7574865 polymorphism was significantly associated with AITD susceptibility [TT vs. GG: OR = 1.63, 95%CI = 1.24-2.15, P Z = 0.0005; TT vs. (TG+GG): OR = 1.55, 95%CI = 1.26-1.91, P Z < 0.0001]. However, the subgroup analysis showed a significant association of STAT4 rs7574865 polymorphism with AITD susceptibility in Asian population, but not in African population. STAT4 rs7574865 polymorphism was significantly associated both with Graves' disease (GD) and Hashimoto's thyroiditis (HT) susceptibility. Conclusion: This meta-analysis showed a significant association between STAT4 rs7574865 polymorphism and AITD susceptibility. However, further studies with larger sample sizes and other ethnicities are still required to confirm the findings.
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Project description:IntroductionType 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 methodsRs7574865 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.ResultsThe 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).ConclusionsThe 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.
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Project description:ObjectiveThe T allele of rs7574865 in STAT4 confers risk of developing autoimmune disorders. However, its functional significance remains unclear. Here we analyze how rs7574865 affects the transcription of STAT4 and its protein expression.MethodsWe studied 201 patients (80% female; median age, 54 years; median disease duration, 5.4 months) from PEARL study. Demographic, clinical, laboratory and therapeutic data were collected at each visit. IL-6 serum levels were measured by enzyme immune assay. The rs7574865 was genotyped using TaqMan probes. The expression levels of STAT4 mRNA were determined at 182 visits from 69 patients using quantitative real-time polymerase chain reaction. STAT4 protein was assessed by western blot in 62 samples from 34 patients. To determine the effect of different variables on the expression of STAT4 mRNA and protein, we performed multivariate longitudinal analyses using generalized linear models.ResultsAfter adjustment for age, disease activity and glucocorticoid dose as confounders, the presence of at least one copy of the T allele of rs7574865 was significantly associated with higher levels of STAT4 mRNA. Similarly, TT patients showed significantly higher levels of STAT4 protein than GG patients. IL-6 induced STAT4 and STAT5 phosphorylation in peripheral blood lymphocytes. Patients carrying at least one T allele of rs7574865 displayed lower levels of serum IL-6 compared to GG homozygous; by contrast the production of C-reactive protein was similar in both populations.ConclusionOur data suggest that the presence of the rs7574865 T allele enhances STAT4 mRNA transcription and protein expression. It may enhance the signaling of molecules depending on the STAT4 pathway.
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