Signal Transducer And Activator Of Transcription 4 Rs7574865 Research Articles

The effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of hepatocellular carcinoma.

Signal transducer and activator of transcription 4 (STAT4) is closely related to liver diseases and affects the processes of inflammation and carcinogenesis by regulating immune responses. A single-nucleotide polymorphism rs7574865 (T > G) in STAT4 has been reported to be associated with the risk of hepatocellular carcinoma (HCC). In addition, hepatitis B virus (HBV) mutations are crucial risk factors for HBV-induced HCC. However, the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC remain unknown. Rs7574865 was genotyped in 846 healthy controls (HCs), 968 chronic hepatitis B (CHB) subjects, 316 liver cirrhosis (LC) subjects and 1021 HCC subjects using Sequenom MassArray. HBV mutations were detected via direct sequencing. Multivariate logistic regression analysis was used to evaluate the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC. We found that the rs7574865 TT genotype was significantly associated with HBeAg seroconversion (TT vs. GG, p = 0.012; TT vs. GT, p = 0.033). The rs7574865 GG genotype was significantly associated with increased risks of CHB (p = 0.048), LC (p = 0.005) and HCC (p < 0.001). The interaction term between rs7574865 and HBV C1913A significantly increased the risk of progression from CHB to HCC (p = 0.038), while the interaction term between rs7574865 and HBV T1674C significantly increased the risk of progression from LC to HCC (p = 0.023).STAT4 rs7574865 is significantly associated with the risks of CHB, LC and HCC. The interactions of rs7574865 with HBV C1913A and T1674C mutations significantly increase the risk of HCC, which have the potential to identify HBV-infected individuals who tend to progress from CHB or LC to HCC.

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

BackgroundVariants 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. ResultsA 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. ConclusionIt 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.

A new discovery of STAT4 single nucleotide polymorphisms associated with hepatocellular carcinoma risk in Chinese Han population: a case-control study.

Background: Hepatocellular carcinoma (HCC) is a common fatal malignant tumor worldwide. Signal transducer and activator of transcription 4 (STAT4) is HCC susceptibility gene identified by genome-wide association study. The purpose of the present study was to determine the association between four candidate single nucleotide polymorphisms (SNPs) in STAT4 genes and HCC risk in Chinese Han population.Methods: A case–control study was conducted to assess the association between STAT4 SNPs and HCC risk in 1011 Chinese Han population. Agena MassARRAY was used to genotype SNPs. The association between SNPs and HCC susceptibility under different genetic models was evaluated by logistic regression analysis. Multifactorial dimension reduction (MDR) analyzed the interaction of ‘SNP–SNP’ in HCC risk. The difference of clinical characteristics between different genotypes was completed by ANOVA.Results: The results showed that STAT4 rs11889341 was significantly associated with HCC risk under multiple genetic models (homozygote: odds ratio (OR) = 0.60, P=0.033; recessive: OR = 0.63, P=0.028; log-additive: OR = 0.83, P=0.032). The results of subgroup analysis showed that STAT4 rs11889341 is significantly associated with HCC risk with participants who were >55 years, male or smoking. Both STAT4 rs7574865 and rs10174238 were significantly associated with HCC risk among participants who were >55 years, smoking or drinking. STAT4 haplotype (Trs11889341Trs7574865) could reduce the risk of HCC. In addition, rs11889341 and rs7574865 were significantly associated with the level of serum ferritin (SF).Conclusion: STAT4 rs11889341, rs7574865 or rs10174238 is potentially associated with HCC risk in Chinese Han population. In particular, rs11889341 showed outstanding association with HCC risk.

Association of STAT4 rs7574865 with Sysceptibility to Juvenile Onset Systemic Lupus Erythematous in Pakistani Population

Association of STAT4 (signal transducer and activator of transcription4) haplotype tagged by single nucleotide polymorphism (SNP) rs7574865 with systemic lupus erythematosus (SLE) was reported in different populations. This study was aimed to investigate a genetic association between STAT4 single nucleotide polymorphism (rs7574865) with susceptibility and clinical features of systemic lupus erythematosus in Pakistani population. A total of 75 clinically diagnosed individuals affected with SLE were enrolled from Children’s Hospital and Institute of Child Health Lahore. Sixty-eight healthy individuals of same ethnicity were also enrolled for this study. Clinical assessment of patients was done with the help of clinical features suggestive for SLE and some diagnostic tests specific for the disease were performed. SNP rs7574865 was genotyped by allele specific tetra ARMS PCR assay to check and compare the genotypic allele frequencies between SLE patients and healthy controls. Different statistical analysis ChiSquare, Fisher’s exact tests and binary Logistic Regression is performed to determine association of risk alleles with SLE in Pakistani population. p value less than >0.05 consider significant. This study showed the frequency of GG (28%), TT (12%), and GT alleles (60%) in SLE patients while controls showed allele frequencies of GG (5%), TT (29%) and GT (64%), respectively. The results showed that GG genotype and G allele in STAT4 rs7574865 was the risk allele for SLE while T allele proved to be the protective one for disease susceptibility when compared with healthy controls genotypic frequencies. This study suggests the strong association of SNP rs7574865 in STAT4 with the risk of SLE in Pakistani population. However, G allele showed no association with organ damage and immune disorder of SLE.

Association between Signal Transducer and Activator of Transcription 4 Genetic Polymorphisms and the Spontaneous Clearance of Hepatitis B Surface Antigen: A Large Population Case Control Study in China

Aim: Several host factors mediating immune response influence susceptibility to Hepatitis B Virus (HBV) infection, ability to clear the virus, and maintenance of a chronic state. Signal Transducer and Activator of Transcription 4 (STAT4) variations are correlated with the risk of developing autoimmune diseases. However, there have been few studies to assess the relationship between STAT4 variations and Hepatitis B surface Antigen (HBsAg) clearance in adults infected with HBV. Our aim was to evaluate the association between genetic variants in STAT4 and HBsAg clearance in a large sample size population. Methods: This case control study included Chronic Hepatitis B (CHB) (n = 1.688), HBsAg Clearance after Treatment (TC) (n = 170), HBV Uninfected (HC) (n = 1.012), and HBsAg Spontaneous Clearance (SC) (n = 1,052) patients. In the CHB group, patients were categorized into four subgroups: the Immune Tolerant (IT), Immune Active (IA), Inactive (IC), and Immune Reactivation (IR) phases, with 97, 855, 198, and 538 patients in each subgroup, respectively. Results: We found that the G allele in STAT4 rs7574865 was more frequent in the CHB and TC groups, compared with the SC group, whereas the STAT4 rs7574865 GG genotype was more frequent in the CHB and TC group, compared with the SC group in the dominant model. However, there was no statistical significance in genotype between TC and CHB, nor between the IT, IA, IC, and IR groups. Conclusions: The prevalence of the minor allele rs7574865 T was higher in subjects with spontaneously cleared HBV infections than in CHB patients.

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

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.

The Association Between STAT4 rs7574865 Polymorphism and the Susceptibility of Autoimmune Thyroid Disease: A Meta-Analysis.

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, PZ = 0.0005; TT vs. (TG+GG): OR = 1.55, 95%CI = 1.26–1.91, PZ < 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.

Multiple genetic variants associated with posttransplantation diabetes mellitus in Chinese Han populations.

Posttransplantation diabetes mellitus (PTDM) is a major complication after solid organ transplantation. This study is to investigate the association of nine genetic variant factors and PTDM in Chinese Han patients. HLA-DP (rs3077, rs9277535), HLA-DQ (rs7453920), signal transducer and activator of transcription 4 (STAT4) (rs7574865), IL-28B (rs12979860, rs8099917, and rs12980275), and IL-18 (rs1946518 and rs187238) were investigated in 260 liver transplant recipients (PTDM vs non-PTDM) by high-resolution melting curve analysis. Serum interleukin (IL)-1β, IL-6, IL-8, IL-17, interferon-γ, inducible protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b were analyzed by a Bio-Plex suspension array system (Bio-Plex Multiplex Immunoassays, Bio-Rad, Hercules, CA, USA). Signal transducer and activator of transcription 4 (rs7574865) T allele and IL-18 (rs1946518) A allele increase the risk for insulin resistance and PTDM. Recipients with STAT4 (rs7574865) T allele are associated with an increased concentration of IL-1β, interferon-γ, monocyte chemoattractant protein, and macrophage inflammatory protein-1b. The genetic variants of STAT4 (rs7574865) and IL-18 (rs1946518) may be new important markers for PTDM.

Association of STAT4 rs7574865 and PTPN22 rs2476601 polymorphisms with rheumatoid arthritis and non-systemically reacting antibodies in Egyptian patients.

The aim of this study was to investigate association of protein tyrosine phosphatase non-receptor type 22 (PTPN22) rs2476601 and signal transducer and activator of transcription 4 (STAT4) rs7574865 polymorphisms with rheumatoid arthritis (RA) susceptibility and to assess potential association with the status of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, serum neopterin, and disease activity. RF, anti-CCP antibodies, and neopterin were assayed in serum of 100 unrelated RA patients and 114 controls. STAT4 rs7574865 G/T and PTPN22 rs2476601 C/T polymorphisms were genotyped by the TaqMan allelic discrimination method. The frequency of STAT4 variant allele was significantly higher in RA patients than in controls (p=0.01), while the variant allele of PTPN22 was identified in only two RA patients, in a heterozygous form and in none of control subjects. The frequency of STAT4 variant allele carrier genotypes (GT+TT) was significantly higher among RA patients than in controls (43.7 vs. 10.5%, p=0.02) and associated with RA under additive and dominant models. The frequency of RF and anti-CCP positivity was significantly higher among RA patients carrying T allele genotypes compared to patients carrying wild genotype (P=0.02 and 0.04, respectively). No significant associations between STAT4 variant and serum neopterin or disease activity parameters were identified. Our study confirmed the association of STAT4 rs7574865 polymorphism with RA and was the first to indicate an association with RF and anti-CCP antibodies positivity. We also found PTPN22 rs2476601 has no role in susceptibility to RA in Egyptian patients.

Lack of Association between STAT4 Single Nucleotide Polymorphisms and Iranian Juvenile Rheumatoid Arthritis Patients

ABSTRACTJuvenile rheumatoid arthritis (JRA) is a common chronic systemic autoimmune disease in children. Single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) gene are suspected to have association with the risk of autoimmune diseases. Previous investigations have indicated that the STAT4 rs7574865 T allele was significantly associated with rheumatoid arthritis. In this study, we aimed to evaluate the association of STAT4 SNPs with JRA in Iranian population. T allele of STAT4 rs7574865 SNP was less frequent in patients than in controls, and the difference was not significant (p = 0.19, OR = 0.72, 95% CI: 0.44 −1.17). In addition, G allele of this SNP was frequent but not significant in JRA patients (p = 0.19, OR = 1.38, 95% CI: 0.85–2.25). Neither alleles nor genotypes of rs7601754 SNP of STAT4 gene demonstrated associations with JRA. We recognize that gene variants of STAT4 did not affect JRA susceptibility in Iranian population.

STAT4 rs7574865 polymorphism in Iranian patients with rheumatoid arthritis

ObjectivesThe gene encoding signal transducer and activator of transcription 4 (STAT4) has been documented to be associated with rheumatoid arthritis (RA) in several populations. The aim of this study was to determine the association of the STAT4 gene polymorphism (rs7574865) with RA in the Iranian population. MethodsThis study included 612 Iranian RA patients and 389 healthy control subjects. For all samples, DNA was genotyped for STAT4 G>T (rs7574865) polymorphism using the MGB TaqMan Allelic Discrimination method. ResultsIn our survey, the frequencies of GG, GT, and TT genotypes were 50%, 41.3%, and 8.7% in RA patients, and 51.4%, 37.5%, and 11.1% in controls (P>0.05), respectively. STAT4 rs7574865 alleles were not associated with the disease risk in the Iranian population (P>0.05). ConclusionsAlthough most studies have proposed STAT4 polymorphisms as a susceptible risk factor for RA, we did not detect any significant association between the STAT4 polymorphism and RA in our study. Population-based studies help to identify genetic determinants of disease susceptibility. Possible explanations for differences in susceptible genetic factors among populations could be different genetic predispositions and contribution of gene–gene or gene–environment interactions.

Polymorphisms in STAT4 and IRF5 increase the risk of systemic sclerosis: a meta-analysis.

Systemic sclerosis (SSc) is the most severe connective tissue disorder. Recent studies have demonstrated that genetic factors may play a role in the development of SSc. The aim of this study was to investigate the association of signal transducer and activator of transcription 4 (STAT4) rs7574865 and interferon regulatory factor 5 (IRF5) rs2004640 polymorphisms with risk of SSc. Case-control studies were obtained from the electronic database of PubMed, Medline, Embase, and CNKI (China National Knowledge Infrastructure) up to December 2013. The association between STAT4 and IRF5 polymorphisms and SSc susceptibility was assessed by pooled odds ratios (ORs) and 95% confidence intervals (CI). Six related studies, including 4746 SSc cases and 7399 healthy controls, were pooled in this meta-analysis. For STAT4 polymorphism, we observed a statistically significant positive association between risk factor T allele carriers and SSc susceptibility (OR = 1.37, 95% CI = 1.27-1.48, P < 0.00001) in the overall population. The presence of limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) scleroderma also showed a significant association with each of the genetic models (P < 0.00001). For IRF5 polymorphism, the T allele was shown to be strongly associated with increased SSc risk (OR = 1.27, 95% CI = 1.17-1.39, P < 0.00001). No significant heterogeneity between studies was found. The results demonstrated that STAT4 rs7574865 and IRF5 rs2004640G/T substitution are associated with a susceptibility to SSc, and they may serve as the SSc genetic susceptibility factor. These data confirmed that genetic polymorphisms may play a role in the development of SSc and have provided new insight into the pathogenesis of SSc.

Application of Various Statistical Models to Explore Gene-Gene Interactions in Folate, Xenobiotic, Toll-Like Receptor and STAT4 Pathways that Modulate Susceptibility to Systemic Lupus Erythematosus.

In view of our previous studies showing an independent association of genetic polymorphisms in folate, xenobiotic, and toll-like receptor (TLR) pathways with the risk for systemic lupus erythematosus (SLE), we have developed three statistical models to delineate complex gene-gene interactions between folate, xenobiotic, TLR, and signal transducer and activator of transcription 4 (STAT4) signaling pathways in association with the molecular pathophysiology of SLE. We developed additive, multifactor dimensionality reduction (MDR), and artificial neural network (ANN) models. The additive model, although the simplest, suggested a moderate predictability of 30 polymorphisms of these four pathways (area under the curve [AUC] 0.66). MDR analysis revealed significant gene-gene interactions among glutathione-S-transferase (GST)T1 and STAT4 (rs3821236 and rs7574865) polymorphisms, which account for moderate predictability of SLE. The MDR model for specific auto-antibodies revealed the importance of gene-gene interactions among cytochrome P450, family1, subfamily A, polypeptide 1 (CYP1A1) m1, catechol-O-methyltransferase (COMT) H108L, solute carrier family 19 (folate transporter), member 1 (SLC19A1) G80A, estrogen receptor 1 (ESR1), TLR5, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), thymidylate synthase (TYMS). and STAT4 polymorphisms. The ANN model for disease prediction showed reasonably good predictability of SLE risk with 30 polymorphisms (AUC 0.76). These polymorphisms contribute towards the production of SSB and anti-dsDNA antibodies to the extent of 48 and 40%, respectively, while their contribution for the production of antiRNP, SSA, and anti-cardiolipin antibodies varies between 20 and 30%. The current study highlighted the importance of genetic polymorphisms in folate, xenobiotic, TLR, and STAT4 signaling pathways as moderate predictors of SLE risk and delineates the molecular pathophysiology associated with these single nucleotide polymorphisms (SNPs) by demonstrating their association with specific auto-antibody production.

Association of PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with rheumatoid arthritis: A meta-analysis update

BackgroundRheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic background. The genes encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) and signal transducer and activator of transcription 4 (STAT4) have been reported to be associated with RA in several ethnic populations. ObjectivesThis work aims to assess the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility through an updated meta-analysis of available case–control studies. MethodsA literature search of all relevant studies published from January 2007 up to December 2014 was conducted using Pubmed and Science Direct databases. The observed studies that were related to an association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility were identified. Meta-analyis of the pooled and stratified data was done and assessed using varied genetic models. ResultsThirty-seven case–control studies with a total of 47 comparisons (29 for PTPN22 rs2476601 polymorphism and 18 for STAT4 rs7574865 polymorphism) met our inclusion criteria. The meta-analysis showed an association between PTPN22 T allele, CT+TT and TT genotypes with RA susceptibility. Furthermore, The meta-analysis showed an association between STAT4 T allele, GT+TT and TT genotypes with RA susceptibility. Stratification of RA patients according to ethnic groups showed that PTPN22 T allele, CT+TT genotypes, STAT4 T allele and STAT4 GT+TT were significantly associated with RA in European, Asian, African subjects, while PTPN22 TT genotype was significantly associated with RA in European but not in Asian and African subjects and STAT4 TT genotype was significantly associated with RA in European and Asian but not in African subject. A subgroup analysis according to the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies revealed that the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility may not be dependent on RF and anti-CCP antibodies. ConclusionsOur meta-analysis demonstrated that PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms confers susceptibility to RA in total subjects and in major ethnic groups. The association may not be dependent on RF and anti-CCP antibodies.

An updated meta-analysis of the signal transducer and activator of transcription 4 (STAT4) rs7574865 G/T polymorphism and rheumatoid arthritis risk in an Asian population

Objectives: Signal transducer and activator of transcription 4 (STAT4) transmits signals induced by the cytokines interleukin (IL)-12, IL-23, and interferon (IFN)-γ, which play an important role in the development of rheumatoid arthritis (RA). Studies have shown conflicting results concerning the association between the rs7574865 G/T polymorphism in the STAT4 gene and RA in an Asian population. We have performed a meta-analysis to examine this relationship.Method: We searched PubMed and WanFang databases for all papers published up to 5 October 2013. Eight case–control studies with 6029 cases and 4685 controls were retrieved based on the search criteria for RA susceptibility related to the STAT4 rs7574865 G/T polymorphism. Risk ratios (RRs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Publication bias was assessed using Begg’s test.Results: A significant association was found between the STAT4 rs7574865 G/T polymorphism and RA risk (e.g. GG+GT vs. TT: RR 0.96, 95% CI 0.95–0.97; GG+TT vs. GT: RR 0.94, 95% CI 0.91–0.97). Subgroup analysis of rheumatoid factor (RF) status revealed a protective relationship between the STAT4 rs7574865 G/T polymorphism and RF+/RF− RA risk. A similar relationship was detected in the anti-cyclic citrullinated peptide (CCP) status subgroup. No clear evidence of publication bias was detected in the overall analysis.Conclusions: Our study indicates that the STAT4 rs7574865 G/T polymorphism was significantly associated with a decreased RA risk in an Asian population.

Association of IRF5 polymorphism with MPO–ANCA-positive vasculitis in a Japanese population

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a Chinese population

AimRheumatoid arthritis (RA) and ankylosing spondylitis (AS) are common systemic autoimmune diseases with genetic and environmental predisposing factors. Signal transducer and activator of transcription 4 (STAT4) transmits signals induced by interleukin-12, interleukin-23 and interferon-γ, which are key cytokines and play important roles in the development of autoimmune diseases. Previous studies confirmed the STAT4 rs7574865 G/T locus to be associated with RA. Thus we conducted a replication study to investigate STAT4 rs7574865 G/T polymorphism and RA/AS susceptibility in a Chinese population. MethodsWe studied STAT4 rs7574865 G/T gene polymorphism in 520 patients with RA, 100 AS patients and 520 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). ResultsWhen the STAT4 rs7574865 GG homozygote genotype was used as the reference group, the GT or GT/TT genotypes were associated with the risk for RA. After stratification analyses, a significantly increased risk for RA associated with the STAT4 rs7574865 GT genotype was evident among the rheumatoid factor (RF)-positive patients, patients with higher erythrocyte sedimentation rate (ESR) level and patients with higher RA disease activity score (DAS28) compared with the STAT4 rs7574865 GG genotype. A significantly increased risk for RA associated with the STAT4 rs7574865 TT genotype was evident among older patients and RF-negative patients compared with the STAT4 rs7574865 GG genotype. STAT4 rs7574865 G/T was not associated with susceptibility to AS. ConclusionThis replication study confirmed that STAT4 rs7574865 G/T polymorphism was associated with the risk of RA. Condensed abstractSTAT4 polymorphisms are associated with rheumatoid arthritis risk.

Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody

Signal transducer and activator of transcription 4 (STAT4) has been recently identified as a susceptibility gene for multiple autoimmune diseases. Here we performed a comprehensive analysis of the association between STAT4 and several different autoimmune disorders to identify potential common inflammatory principles behind this association. Our meta-analysis revealed that the STAT4 rs7574865 polymorphism is associated with four autoimmune diseases with systemic pathology, including systemic lupus erythematosus (OR = 1.52; 95% CI = 1.48 - 1.56, P<1.0 × 10(-16)), rheumatoid arthritis (OR = 1.27; 95% CI = 1.21 - 1.33, P < 1.00 × 10(-16)), systemic sclerosis (OR = 1.38; 95% CI = 1.27 - 1.50, P < 1.44 × 10(-14)), and primary Sjogren's syndrome (OR = 1.32; 95% CI = 1.01 - 1.73, P = 4.40 × 10(-2)), while no association was found with type I diabetes, juvenile idiopathic arthritis, ulcerative colitis and Crohn's disease. Furthermore, the stratified meta-analysis also demonstrate that the STAT4 rs7574865 polymorphism is associated with the presence of autoantibodies with systemic reactivity (anti-ds-DNA antibodies) in SLE patients (OR = 1.37; 95% CI = 1.21 - 1.56, P = 1.12 × 10(-6)). However, no such specific association was seen in RA with regard to the presence of non-systemically reacting antibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Taken together, these results suggest that STAT4 polymorphisms are associated with autoimmune diseases which are characterized by a systemic pathology and anti-dsDNA antibody.

Association between polymorphism in STAT4 gene and risk of rheumatoid arthritis: A meta-analysis

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease, affecting 1% of the population worldwide. Single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) gene are suspected to have some relationship with the risk of RA. This meta-analysis aimed to evaluate the relationship between the polymorphism rs7574865 in STAT4 gene with RA and also examine whether the associations that have been reported in these studies differ between ethnic groups. We retrieved the relevant articles from PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases. The odds ratios (ORs) and their 95% confidence intervals (95% CIs) associated with the minor T allele of STAT4 rs7574865 SNP were extracted from the published studies and included in the analysis. Meta-analyses were performed on the total data set and separately for the major ethnic groups and RF and anti-CCP status. All analyses were performed using the Stata software. Twenty-three articles were included in the present analysis. Meta-analysis showed an association between the STAT4 polymorphism and RA in all subjects (OR=1.299, 95%CI=1.230-1.371, P<0.001). Stratified analyses indicated that the STAT4 rs7574865 T allele was significantly associated with RA in both Caucasians and Asians, in both positive and negative RF patients versus controls, also significantly in the presence of anti-CCP, both positive and negative. As for genotypes of rs7574865 polymorphism, all the results were significant, no matter in total subjects or stratified analyses by ethnic groups or by RF and anti-CCP status. Genetic polymorphism rs7574865 in STAT4 gene might be associated with RA susceptibility in total subjects, major ethnic groups and different status of anti-CCP or RF.

Polymorphisms of STAT4 and the risk of inflammatory bowel disease: A case-control study in Chinese Han population

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor involved in the signaling pathways of several cytokines, playing an essential role in the development of inflammation in various immune-mediated diseases. Genetic association studies have shown that the STAT4 gene was significantly associated with inflammatory bowel disease (IBD) in Spanish and Caucasian populations. However, these associations in other ethnic populations remain unknown. In the present study, we evaluated the role of the STAT4 rs7574865 and rs7582694 polymorphisms on IBD in 562 unrelated Chinese Han subjects by assessing distributions of genotypes and allele frequencies. Results showed that neither rs7574865 [Crohn's disease (CD): P=0.66, odds ratio (OR) = 0.95, 95% confidence interval (CI) 0.74-1.21; ulcerative colitis (UC): P=0.43, OR=0.85, 95% CI 0.56-1.28; IBD: P=0.52, OR=0.93, 95% CI 0.73-1.17] nor rs7582694 (CD: P=0.40, OR=1.12, 95% CI 0.86-1.44; UC: P=0.50, OR=0.86, 95% CI 0.56-1.33; IBD: P=0.62, OR=1.06, 95% CI 0.83-1.36) was significantly associated with IBD, although the genotype frequency of rs7574865 varied in patients and the controls. In conclusion, our data did not support that STAT4 variants contribute to IBD susceptibility in the Chinese Han population.