STAT4 Gene Polymorphism Research Articles

STAT4 gene polymorphisms in human diseases

STAT4 gene polymorphisms in human diseases

Association of STAT4 Gene Polymorphisms (rs10181656, rs7574865, rs7601754, rs10168266) and Serum STAT4 Levels in Age-Related Macular Degeneration.

To investigate the association between STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) gene polymorphisms and STAT4 serum levels in patients with age-related macular degeneration. The study included 150 individuals with early AMD, 150 individuals with exudative AMD, and 200 healthy subjects. DNA was extracted from peripheral blood leukocytes using the DNA salting-out method, and the genotyping was performed using a real-time polymerase chain reaction (RT-PCR) method. STAT4 serum levels were evaluated using the ELISA method. Statistical analysis was performed using "IBM SPSS "Statistics 29.0" software". The study revealed no statistically significant differences in the distribution of genotypes and alleles for the STAT4 polymorphisms (rs10181656, rs7574865, rs7601754, and rs10168266) between patients with AMD and the control group. Similarly, a gender-based analysis did not yield any significant differences in the genotype or allele frequencies. Age group comparisons also showed no statistically significant variations in the presence of these STAT4 polymorphisms between AMD patients and the control group. However, notably, individuals with exudative AMD displayed lower levels of serum STAT4 in comparison to the control group (median (IQR): 0.118 (0.042) vs. 0.262 (0.385), p = 0.005). Investigating STAT4 gene polymorphisms (rs10181656, rs7574865, rs7601754, and rs10168266) did not reveal a significant association with AMD. However, further analysis demonstrated intriguing findings regarding serum STAT4 levels. Exudative AMD patients with at least one G allele of the STAT4 rs10181656 exhibited significantly lower serum STAT4 levels than the control group subjects (p = 0.011). Similarly, those with at least one T allele of STAT4 rs10168266 had lower serum STAT4 levels compared to the control group subjects (p = 0.039). These results suggest a potential link between specific STAT4 genotypes and serum STAT4 levels in exudative AMD patients, shedding light on a novel aspect of the disease.

Optic Neuritis: The Influence of Gene Polymorphisms and Serum Levels of STAT4 (rs10181656, rs7574865, rs7601754, rs10168266).

The aim of the study was to evaluate the associations of STAT4 (rs10181656, rs7574865, rs7601754, rs10168266) gene polymorphisms and STAT4 serum level in patients with optic neuritis. Eighty-one subjects with optic neuritis (ON) and 158 healthy subjects participated in the study. Genotyping was performed using real-time polymerase chain reaction to obtain data. STAT4 serum level was determined using the ELISA method. Statistical analysis revealed that STAT4 rs7574865 allele G was statistically significantly more frequent in patients with ON and multiple sclerosis (MS) than in the control group (84.38% vs. 65.93%, p = 0.003). STAT4 rs10168266 allele C was statistically significantly more frequent in the ON group with MS than in the control group (89.06% vs. 71.75%, p = 0.003). The haplotypes G-G-A-C and C-T-A-T of STAT4 (rs10181656, rs7574865, rs7601754, rs10168266) were associated with an 11.5- and 19.5-fold increased odds of ON occurrence (p = 0.003; p = 0.008, respectively). In optic neuritis without MS occurrence, STAT4 (rs10181656, rs7574865, rs7601754, rs10168266) haplotypes G-G-A-C and C-T-A-T were found to be associated with 32.6- and 9-fold increased odds of ON without MS (p = 0.002, p = 0.016, respectively). The current findings may indicate a risk role of STAT4 (rs10181656, rs7574865, rs7601754, rs10168266) G-G-A-C and C-T-A-T haplotypes in the occurrence of optic neuritis.

Association of IRF5 (rs2004640), STAT4 (rs7574865), and TNFAIP3 (rs6920220, rs2230926) gene polymorphisms with primary Sjögren's syndrome and its complication, MALT-lymphoma

In recent years, more and more data have emerged confirming the contribution of non-HLA genetic markers to the predisposition to thedevelopment of Sjögren's syndrome (SS) and its severe complication, MALT-lymphoma. Objective: to study the association of polymorphisms of IRF5 (rs2004640), STAT4 (rs7574865), and TNFAIP3 (rs6920220, rs2230926) genes with predisposition to the development of SS and MALT-lymphoma. Materials and methods. The study included 80 patients with SS and 103 individuals in the control group. Sixteen patients were diagnosed with MALT-lymphoma. Genotyping of polymorphisms of IRF5 (rs2004640), STAT4 (rs7574865), TNFAIP3 (rs6920220, rs2230926) genes was performed by real-time polymerase chain reaction using original allele-specific probes labeled with different fluorescent labels. Results and discussion. The distribution of genotypes and alleles of the STAT4 gene differed statistically significantly in the study and control groups of patients (p = 0.0005 and p = 0.0001, respectively). The presence of the homozygous TT genotype increased the risk of developing SS more than eightfold compared to TG+GG genotypes (odds ratio, OR=8.2; 95 % confidence interval, CI 2.5–30.0; p=0.0001)]. The polymorphism of the TNFAIP3 rs2230926 gene was also associated with the risk of developing SS: the presence of the TG genotype significantly increased the probability of developing SS compared to the TT genotype (OR 6.4; 95% CI 1.2–44.3; p = 0.01). The development of MALT-lymphoma was associated with the rs6920220 polymorphism of the TNFAIP3 gene. In 10 out of 16 patients with MALT-lymphoma (62.5 %) at least one minor A allele (AA+GA) was detected, while in patients without MALT-lymphoma only in 32.8 % of patients at least one minor A allele was detected (OR=3.4, CI 1.1–10.7; p=0.03). In addition, a correlation was found between the rs7574865 TT genotype of the STAT4 gene and the risk of developing severe leukopenia in SS, which was significantly more frequent in carriers of the TT genotype than in individuals with the GG + GT genotype (OR 4.9; 95 % CI 1.7–14.4; p = 0.004). Polymorphism of the IRF5 gene (rs2004640) was not associated with risk of developing SS or with clinical manifestations of the disease. Conclusion. Polymorphisms rs7574865 of STAT4 gene, rs6920220, rs2230926 of TNFAIP3 gene are associated either with the risk of developing SS or with severe complications of the disease, MALT-lymphoma and leukopenia.

The role of polymorphisms rs12218 of the <i>SAA1</i> gene, rs1205 of the <i>CRP</i> gene, and rs7574865 of the <i>STAT4</i> gene in the formation of predisposition to panniculitis in the Russian cohort of patients (pilot study)

Objective: to study the role of SAA1, CRP and STAT4 gene polymorphisms in the development of panniculitis (PN) and their relationship with clinical and laboratory parameters in the Russian cohort of patients.Patients and methods. The study included 74 patients (67 women and 7 men aged 15 to 76 years) with diagnosis of PN. In addition to the general clinical examination, immunological and histological studies, computed tomography of the chest, and tuberculin tests were performed. For genetic study, two groups of patients were formed: with septal PN (SPN, n=26), represented by erythema nodosum (EN) and with lobular PN (LPN, n=48), including predominantly with idiopathic LPN (iLPN, n= 18) and other rare variants (n=30). As a control, the results of DNA genotyping of 142 healthy non-related individuals were used. Genotyping of polymorphisms rs12218 of the SAA1 gene, rs1205 of the CRP gene, and rs7574865 of the STAT4 gene was performed by the allele-specific real-time polymerase chain reaction.Results and discussion. Significant differences were found between the groups in terms of age and duration of the disease. Patients with SPN were younger than those with LPN (p=0.013), had a shorter duration of the disease (p=0.001), and a lower ESR (p=0.001). Carriers of the TT genotype of the SAA1 gene polymorphism were twice as likely to develop LPN as compared to controls (odds ratio, OR 2.25; 95% confidence interval, CI 1.04–4.87; p=0.038), and this genotype was regarded as a risk factor. For patients with SPN, a significant risk factor was identified in the form of carriage of the mutant TT genotype of the CRP gene polymorphism. This genotype increased the predisposition to the development of EN by 4 times compared with the control (OR 4.39; 95% CI 1.26–14.11; p=0.009). There was a 6-fold increase in the risk of developing EN in carriers of the TT mutant genotype and the T allele of the STAT4 gene polymorphism compared with the control (OR 5.89; 95% CI 1.14–31.75; p=0.016 and OR 2.07; 95 % CI 0.99–4.19, p=0.030, respectively). Comparison of the frequencies of the T allele of the SAA1 gene polymorphism in the groups with EN and with iLPN revealed a higher frequency of the SAA1TT genotype and the SAA1T allele in iLPN than in EN (66.7 and 26.9%, p=0.066; 88.5 and 55.8 %, p=0.016, respectively).Conclusion. The present study confirms the involvement of genetic factors, in addition to generally recognized environmental factors, in the pathogenesis of inflammatory diseases of adipose tissue. Polymorphisms of the SAA1, CRP, and STAT4 genes play a role in the formation of a genetic predisposition to the main clinical phenotypes of PN.

Role of signal transducer, and activator of the transcription 4 (STAT4) gene polymorphism as predictive marker for type-1 autoimmune hepatitis

Introduction: Autoimmune hepatitis (AIH) is one of autoimmune disorder with complex pathophysiology. Many genes involved in lethal autoimmune hepatitis disorder including STAT4 gene. The aim of this study is to determine STAT4 gene polymorphisms and relation of SNPs with disease severity among AIH patients. Method: One hundred AIH patient which diagnosed by clinically, ANA and ASMA and 100 control age matched healthy children were enrolled in this study. Patients' blood samples (5mL) were taken and split into two tubes, one tube used for immunological and clinical parameters and the second containing EDTA for PCR analysis. The first tubes were then left at room temperature for 10 minutes before being centrifuged (3500 rpm). After that, the serum was isolated the both tubes stored at -70°C until analysis, biochemical parameters were measured in full automated biochemistry analyzer while, IgG, ANA and ASMA was investigated using the enzyme-linked immunosorbent assay (ELISA) commercially available kits (Bioneer, Korea), while the STAT4 (rs7574865, rs7582694) gene was investigated using RFLP PCR How, and the commercially available kits (Bioneer, Korea).

The STAT4 SNP (rs7574865) and systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease affecting several systems and organs in the body. The association of STAT4 transcription factor with SLE risk remains unclear. Objectives: The aim of this study was to investigate the association of STAT4 gene polymorphism (rs7574865) with the incidence of SLE. Patients and Methods: One hundred and sixty participants (80 patients with SLE and 80 healthy individuals) were included in this study. Gene analysis was conducted by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in peripheral blood samples. Results: Fifty-seven percent (n=45) of patients with SLE had SLE disease activity index (SLEDAI) above six and had active disease. In the SLE group, the frequency of G and T alleles were 81% and 19%, respectively. Moreover, 72.50% (n=58) of patients carried the GG genotype, 17.5% (n=14) had the GT genotype and 10.1% (n=8) carried the TT genotype. There was no significant difference between allele frequency and genotypic distribution for rs7574865 polymorphism (P>0.05) between SLE and control groups. Significant differences were observed between the distribution of genotypes and clinical manifestations including leukopenia (P=0.04), pulmonary (P=0.01) and ophthalmic (P=0.049) problems. The T allele with an odd ratio of 1.47 and confidence interval of 0.80 to 2.6 could increase the risk of SLE; however, it was not statistically significant (P=0.20). Conclusion: The T allele and TT genotype of the STAT4 rs7574865 polymorphism could increase the risk of lupus; however, these observations were not statistically significant.

STAT4 gene polymorphism as a risk factor for hepatocellular carcinoma on top of chronic hepatitis C

BackgroundSingle-nucleotide polymorphism in the STAT4 gene was strongly associated with the risk of hepatocellular carcinoma (HCC) progression in patients chronically infected with hepatitis C virus (HCV).ObjectiveTo study the effect of STAT4 gene (rs7574865) polymorphism on HCC in complicating chronic hepatitis C.Patients and methodsOne hundred and fifty individuals were divided into three groups. The studied participants were divided into three groups. Group I: 50 apparently healthy individuals served as controls. They were completely free clinically with normal laboratory investigations, normal abdominal ultrasonography, and no history of liver and renal disease. Group II: 50 chronic HCV patients confirmed by HCV-antibodies and PCR HCV RNA analysis. Group III: 50 HCV-induced HCC patients confirmed by computed tomography and serum alpha-fetoprotein. Most of the patients are males with a mean age of 54 years. Real-time PCR analysis to determine STAT4 (rs7574865) gene polymorphism was performed on DNA extracted from all the studied participants.ResultsComparing the three studied groups, there was highly significant statistical difference regarding genotype and allele frequency distribution with a GG genotype of 20% in the control group, 46% in the HCV group, and 56% in the HCC group with a P value less than 0.001. GT genotype is 50% in the control group, 44% in the HCV group, and 38% in the HCC group. There were statistically significant differences in STAT4 (rs7574865) allele frequencies between the patient group (HCC and HCV as one group) and the control group (P < 0.001) [GG: odds ratio (OR)=9.562, 95% confidence interval (CI)=3.204–28.541, GT: OR = 3.075, 95% CI = 1.141–8.290]. Allele association study revealed a significant risk association between allele type and cancer development (OR = 3.066, 95% CI = 1.861–5.053).ConclusionThe results suggested that STAT4 (rs7574865) GG genotype is associated with HCC development in Egyptians with chronic HCV infection.

Association between STAT4 gene polymorphism and type 2 diabetes risk in Chinese Han population

BackgroundEvidence from genetic epidemiology indicates that type 2 diabetes (T2D) has a strong genetic basis. Activated STAT4 has an inflammatory effect, and STAT4 is an important mediator of inflammation in diabetes. Our study aimed to study the association between STAT4 single nucleotide polymorphisms (SNPs) and T2D susceptibility in Chinese Han population.MethodsWe conducted a 'case–control' study among 500 T2D patients and 501 healthy individuals. 5 candidate STAT4 SNPs were successfully genotyped. The association between SNPs and T2D susceptibility under different genetic models was evaluated by logistic regression analysis. ‘SNP-SNP’ interaction was analyzed and completed by multi-factor dimensionality reduction (MDR). Finally, we evaluated the differences of clinical characteristics under different genotypes by one-factor analysis of variance.ResultsThe overall results showed that STAT4 rs3821236 was associated with increasing T2D risk under allele (OR 1.23, p = 0.020), homozygous (OR 1.51, p = 0.025), dominant (OR 1.36, p = 0.029), and additive models (OR 1.23, p = 0.020). The results of stratified analysis showed that rs3821236, rs11893432, and rs11889341 were risk factors for T2D among participants ≤ 60 years old. Only rs11893432 was associated with increased T2D risk among female participants. There was also a potential association between rs3821236 and T2D with nephropathy risk. STAT4 rs11893432, rs7574865 and rs897200 were significantly associated with lysophosphatidic acid, cystatin C and thyroxine t4, respectively.ConclusionThe genetic polymorphisms of STAT4 is potentially associated with T2D susceptibility of Chinese population. In particular, rs3821236 is significantly associated with T2D risk both in the overall and several subgroup analyses. Our study may provide new ideas for T2D individualized diagnosis/protection.

Association of FCN2 gene rs3124954 and STAT4 gene rs7582694 polymorphisms with juvenile onset systemic lupus erythematosus and lupus nephritis in a sample of Egyptian children

BackgroundJuvenile onset SLE (joSLE) is multifactorial autoimmune inflammatory disease with multiple genetic liabilities. Lupus nephritis (LN) is one of the major complications of SLE. FCN2 and STAT4 gene polymorphisms are potentially linked to SLE and LN susceptibility. Aim of the workWe aimed to assess the association of FCN2 polymorphism (rs3124954) and STAT4 polymorphism (rs7582694) with risk of developing joSLE and associated LN. MethodologyOur study included 100 SLE patients, 100 LN patients and 100 matched healthy controls. FCN2 polymorphism (rs3124954) and STAT4 polymorphism (rs7582694) were genotyped using real time PCR while STAT4 protein serum levels were measured utilizing ELISA technique. ResultsThe frequency of the major C allele of FCN2 rs3124954 genotype was significantly higher while the minor T allele was significantly decreased in joSLE patients than in control subjects. The patients carrying CC genotype showed 3.7-fold elevated risk for joSLE compared to minor allele T carriers (TT and CT genotypes) under recessive model, while FCN2 rs3124954 genotypes showed no significant association with LN under any genetic model. The frequency of STAT4 rs7582694 C allele was significantly higher in joSLE patients compared to healthy subjects (p = 0.02) and in LN patients compared to joSLE only patients (p = 0.03). In LN, STAT4 rs7582694 C allele was associated with advanced stages of the disease (p = 0.02). ConclusionOur results suggested that FCN2 rs3124954 SNP minor T allele has protective tendency towards joSLE. STAT4 (rs7582694) SNP minor C allele is associated with increased risk of joSLE and its associated LN.

The rs7574865 polymorphism of the &lt;i&gt;STAT4&lt;/i&gt; gene and risk of early rheumatoid arthritis development (the REMARKA study)

The aim of the study was investigation of association of the rs7574865 polymorphism of STAT4 gene (Signal Transducer and Activator of Transcription 4, a family of signal transduction and transcription activation molecules 4) with very early rheumatoid arthritis (RA) in Russian patients, and the study of the relationship of "phenotype – genotype", particularly of positivity for antibodies to cyclic citrullinated peptides (ACCP), their concentration, the presence of erosive joint damage at inclusion in patients the study with the STAT4 gene polymorphism. Material and methods. The study was conducted in the framework of the program REMARKA (Russian study of Methotrexate and biological drugs in Early active Arthritis). 85 patients with very early RA with a duration of symptoms no more than 6 months, not receiving disease modifying anti-rheumatic drugs (DMARD) and biologicals were included. Results and discussion. The analysis of the distribution of genotypes and alleles of STAT4 rs7574865 polymorphism showed that the frequencies of g/G, G/T and T/T genotypes differ at the level of the prominent tendency to statistical significance between patients with RA and the control group (p=0.05). The frequency of minor allele T in RA is significantly higher than that in the control group, and this allele is associated with a predisposition to RA [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.1–2.8; p=0.03]. In the study of the "genotype – phenotype" relationship, STAT4 gene polymorphism correlated with erosive joint damage (r2=0.289; p=0.008). In carriers of the homozygous genotype TT, the number of erosions at inclusion in the study was significantly higher compared with carriers of genotypes GG/GT (median 5.50 [0.754; 7.5] and 0.00 [0.00; 2.00], respectively; p=0.003). The risk of erosion is also associated with the polymorphism of the STAT4 gene (OR 8.6; 95% CI 1.0–204.9; p=0.03). A difference of the ACCP level depending on STAT4 gene polymorphism was revealed: carriers of at least one minor allele T (G/T+T/T) had significantly higher concentration of ACCP than that in carriers of homozygous GG genotype: 248.97±151.00 and 179.51±147.01 U/ml, respectively; p=0.048).Conclusion. The study showed that in Russian patients with very early RA, the STAT4 gene rs7574865 polymorphism is associated with both predisposition to the disease and prognostically unfavorable manifestations (phenotypes) of the disease, namely, with the development of erosion in the early stages of the disease and an increase of the ACCP level.

Studying the Association between STAT4 Gene Polymorphism and Susceptibility to Rheumatoid Arthritis Disease: An Updated Meta-Analysis.

STAT4 is a transcription factor that plays a role in various cytokine signaling pathways and in T cell subsets differentiation. Several studies have reported STAT4 gene polymorphism in association with various autoimmune diseases. To evaluated the association between STAT4 rs7574865 SNP and RA risk by meta-analysis. Two major databases, namely Scopus and PubMed, were searched to find studies investigating the STAT4 polymorphism and RA in different populations up to November 2017. Association between STAT4 polymorphism and RA were analyzed using pooled odds ratio (OR) and their corresponding 95% CI. In this meta-analysis, 21 population studies (16 papers) comprising 15,732 cases and 15641 healthy subjects evaluating the STAT4 gene rs7574865 SNP were included based on inclusion criteria. Herein, we found a significant positive association between minor T allele as well as different genotypes with the risk of RA. In summary, this study revealed an association between STAT4 gene rs7574865 SNP and risk of RA.

Association of ITGAM, TNFSF4, TNFAIP3 and STAT4 gene polymorphisms with risk of systemic lupus erythematosus in a North Indian population.

Several susceptibility genes have been associated with systemic lupus erythematosus (SLE) across different populations worldwide. However, data on association between genetic polymorphisms and SLE from Indian population is scarce. We aimed to replicate the association of single nucleotide polymorphisms (SNPs) in ITGAM, TNFSF4, TNFAIP3 and STAT4 genes with susceptibility to SLE in a North Indian population. Three hundred and ninety-four SLE patients and 583 unrelated healthy controls of the same ethnic background were enrolled. All samples were genotyped for SNPs in ITGAM (rs1143679), TNFSF4 (rs2205960), TNFAIP3 (rs5029939) and STAT4 (rs7574865) using TaqMan genotyping assay. At allele level, significant association with susceptibility to SLE was detected with polymorphisms in ITGAM (A vs. G, odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.30-2.30, p < 0.001), TNFSF4 (T vs. G, OR = 1.33, 95% CI = 1.08-1.64, p < 0.01), TNFAIP3 (G vs. C, OR = 1.91, 95% CI = 1.27-2.85, p < 0.01) and STAT4 (T vs. G, OR = 1.38, 95% CI = 1.13-1.69, p < 0.01). All four SNPs were associated with SLE under a dominant model with an OR of 1.47 (95% CI = 1.07-2.04, p < 0.05) for ITGAM, 1.30 (95% CI = 1.01-1.69, p < 0.05) for TNFSF4, 1.90 (95% CI = 1.25-2.90, p < 0.01) for TNFAIP3 and 1.38 (95% CI = 1.06-1.78, p < 0.05) for STAT4. Under a recessive model, significant association was found with ITGAM (OR = 4.87, 95% CI = 2.17-10.91, p < 0.001), TNFSF4 (OR = 1.84, 95% CI = 1.13-3.00, p < 0.05) and STAT4 (OR = 1.82, 95% CI = 1.19-2.77, p < 0.01). In conclusion, single nucleotide polymorphisms in ITGAM, TNFSF4, TNFAIP3 and STAT4 genes are associated with susceptibility to SLE in a North Indian population.

STAT4 gene polymorphism in two major autoimmune diseases (multiple sclerosis and juvenile onset systemic lupus erythematosus) and its relation to disease severity

BackgroundMultiple sclerosis (MS) and systemic lupus erythematosus (SLE) are chronic autoimmune mediated diseases with strong genetic and environmental components. The aim of this study is to evaluate the association of STAT4 gene polymorphism with multiple sclerosis (MS) and juvenile onset systemic lupus erythematosus (JO-SLE) and its relation to disease severity.MethodsGroup 1 consisted of 40 MS patients while group 2 included 40 JO-SLE patients. Forty healthy volunteers (controls) were included in this study. STAT4 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).ResultsThe STAT4 CC genotype and GC genotype frequencies were significantly more detected in MS and JO-SLE patients than in controls. The frequency of the STAT4 C allele was significantly higher in patients with MS and those with JSLE compared to controls. Malar rash, photosensitivity, and hair falling were significantly more detected in CC subtype. Malar rash, photosensitivity, and hair falling were significantly more detected in CC subtype. Increased 24-h protein in urine (mg/24 h) and ANA positivity, anti-ds-DNA, anti Sm antibodies’ detection and decreased C3 and C4 levels showed a significantly difference in CC patients. Meanwhile, only increased 24-h protein in urine (mg/24 h) and ANA positivity were significantly more detected in GC patients. STAT4 CC genotype showed a significant increase in the SLE activity index (SLEAI) score and damage index as compared to the STAT4 GG genotype patients. No significant difference was detected in MS Kurtzke’s Expanded Disability Status Scale (EDSS) comparing different STATE 4 genotypes.ConclusionsSTAT4 polymorphism was significantly associated with MS and JO-SLE. Though homozygous JO-SLE patients are more risky for severe disease manifestations, homozygous MS patients are not risky for severe disease disability.

Signal transducer and activator of transcription 4 in liver diseases.

STAT4 is a member of the signal transducer and activator of transcription (STAT) family of molecules that localizes to the cytoplasm. STAT4 regulates various genes expression as a transcription factor after it is phosphorylated, dimerizes and translocates to the nucleus. STAT4 activation is detected virtually in the liver of several mouse models of liver injury, as well as the human liver of chronic liver diseases. STAT4 gene polymorphism has been shown to be associated with the antiviral response in chronic hepatitis C and drug-induced liver injury (DILI), primary biliary cirrhosis (PBC), HCV-associated liver fibrosis and in hepatocellular carcinoma (HCC). However, the roles of STAT4 in the pathogeneses of liver diseases are still not understood entirely. This review summarizes the recent advances on the functional roles of STAT4 and its related cytokines in liver diseases, especially in regulating hepatic anti-viral responses, inflammation, proliferation, apoptosis and tumorigenesis. Targeting STAT4 signaling pathway might be a promising strategy in developing therapeutic approaches for treating hepatitis in order to prevent further injury like cirrhosis and liver cancer.

STAT4 gene polymorphism and risk of chronic hepatitis B-induced hepatocellular carcinoma.

STAT4 is a latent cytosolic factor that encodes a transcription factor transmitting signals stimulated by cytokines. Previous studies with different study designs in diverse ethnic populations have assessed the influence of STAT4 rs7574865 polymorphism on HBV-induced HCC risk. The aim of the current study was to investigate the effects in a larger sample. The individual reports published up to Dec. 30, 2013 were systematically identified by searching the PubMed and Embase databases. To combine the OR and corresponding 95% CI, we used the fixed effects model during meta-analysis. Based on eight independent populations with a total of 5,719 cases and 6,525 controls, we found a slightly reduced risk of HBV-induced HCC in individuals with the minor T allele compared with individuals with the common G allele (T versus G: OR = 0.87, 95% CI = 0.82-0.91, P(Het) = 0.974). Similar reductions were also indicated in all subgroups. The combined data indicate that STAT4 rs7574865 polymorphism may be associated with significantly reduced risk of HBV-induced HCC in Asian.

Retraction

Retraction: Zhou T‐B, Jiang Z‐P, Qin Y‐H, Zhou J‐F. Association of STAT4 gene polymorphism with systemic lupus erythematosus / lupus nephritis risk. Nephrology. 2014; DOI: 10.1111/nep.12264 [Epub ahead of print].The above article, published online on 16 April 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Peter Kerr and Wiley Publishing Asia Pty Ltd. The retraction has been agreed upon due to a case of duplicate submission by the authors to both Modern Rheumatology and Nephrology.

Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population.

The STAT4 gene encodes a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. The aim of this study was to explore the association of STAT4 polymorphism with Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). A total of 1048 autoimmune thyroid diseases (AITDs) patients (693 with GD and 355 with HT) and 909 age- and gender-matched controls were examined. STAT4 polymorphisms (rs7574865/rs10181656/rs7572482) were genotyped by multiplex polymerase chain reaction (PCR) and ligase detection reaction (LDR). The results indicated that the frequencies of rs7574865 genotypes in patients with GD differed significantly from the controls (p = 0.028), the T allele frequency of GD patients was also significantly higher than the controls (p = 0.020). The genotypes of rs10181656 differed significantly in GD patients from controls (p = 0.012); G allele frequencies were significantly higher in AITD patients than the controls (p = 0.014 and 0.031, respectively). The frequencies of haplotype GC with GD and HT patients were significantly lower than their controls (p = 0.015 and 0.030, respectively). In contrast, the frequencies of haplotype TG with GD and HT patients were significantly higher than their controls (p = 0.016 and 0.048, respectively). These findings strongly suggest that STAT4 rs7574865/rs10181656 polymorphisms increase the risk of AITD in a Chinese population.

Retracted Association of STAT4 gene polymorphism with systemic lupus erythematosus / lupus nephritis risk.

The association of STAT4 gene polymorphism with systemic lupus erythematosus (SLE) / lupus nephritis (LN) results from the published studies is still conflicting. This meta-analysis was performed to evaluate the relationship between STAT4 rs7574865, rs16833431, rs11889341, rs8179673, rs10168266, rs7582694, rs3821236, rs7601754 gene polymorphism and SLE / LN, and to explore whether STAT4 gene polymorphism could become a predictive marker for SLE / LN risk. Association studies were identified from the databases of PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) as of September 1, 2013, and eligible investigations were synthesized using meta-analysis method. 24 investigations were identified for the analysis of association between STAT4 gene polymorphism and SLE, consisting of 31190 patients with SLE and 43940 controls. In STAT4 rs7574865, there was a marked association between T allele or TT genotype and SLE susceptibility (T: OR=1.53, 95% CI: 1.30-1.79, P<0.00001; TT: OR=1.60, 95% CI: 1.34-1.92, P<0.00001), and GG homozygous was associated with SLE risk (OR=0.62, 95% CI: 0.51-0.75, P<0.00001). Furthermore, rs8179673, rs7582694, or rs3821236 minor allele frequency was associated with the risk of SLE, but this association was not found in rs16833431, rs11889341, rs10168266, rs7601754, however, the number of included studies was small and the results were less robust. In addition, STAT4 rs7574865 gene polymorphism was not associated with the LN risk. Our results indicate that T allele or TT homozygous is a significant risk genetic molecular marker to predict the SLE susceptibility and GG genotype is a valuable marker to against the SLE risk, but the association was not found for LN. However, more investigations are required to further clarify the association of the T allele or TT homozygous with SLE / LN susceptibility.

AB0005 Investigation of juvenile idiopathic arthritis susceptibility loci: results from a greek population

BackgroundRheumatoid Arthritis (RA) shares some similar clinical and pathological features with juvenile idiopathic arthritis (JIA) [1], an autoimmune disease characterized by chronic arthritis. The strategy of studying the putative role...