STAT4 Polymorphisms Research Articles

The impact of polymorphisms in STAT6 on treatment outcome in HCV infected Taiwanese Chinese

Genetic polymorphisms observed in various disease states associated with sensitivity or resistance to specific treatments have been a robust area of investigation for decades, with the potential to allow clinicians to make evidence-based decisions on the appropriate course of treatment. This study aimed to evaluate whether genetic polymorphisms of the signal transducer and activator of transcription 6 gene (STAT6) could be associated with a sustained virological response (SVR) among patients infected with hepatitis C virus genotypes 1 and 2 (HCV-1 and HCV-2) who were treated with peginterferon plus ribavirin (PEG-IFNα-RBV). We analyzed the associations between SVR to PEG-IFNα-RBV therapy and 4 single nucleotide polymorphisms (SNPs) in STAT6. This study included Taiwanese Chinese patients infected with either HCV-1 (n = 265) or HCV-2 (n = 195) in the presence or absence of an SVR. Among the STAT6 SNPs examined, the dosage effect of the A allele and allele frequency in rs1059513 were inversely correlated with SVR in patients infected with HCV-1 (P = 0.0179 and P = 0.0235, respectively). This effect was not observed in patients infected with HCV-2. The GG, GGG, and GGGC STAT6 haplotypes comprising 2, 3, and 4 SNPs (rs1059513, rs703817, rs324015, and rs3024974) were found to be associated with SVR, and their presence may increase the probability of a successful treatment outcome in patients infected with HCV-1 (P = 0.0273, 0.0352, and 0.0368, respectively). Moreover, a multivariate logistic regression model for predicting an SVR revealed that the presence of the GGGC haplotype carriers mutually affected the outcome of PEG-IFNα-RBV treatment. The presence of STAT6 SNPs and the association with SVR demonstrated that STAT6 polymorphisms might influence the therapeutic outcomes of patients infected with HCV-1 under standard-of-care (SOC) treatment.

STAT4 is a Genetic Risk Factor for Systemic Sclerosis in a Chinese Population

Systemic sclerosis (SSc) is an immune-mediated and complex genetic disease. An association of single-nucleotide polymorphisms (SNPs) in the STAT4 gene with SSc has been reported in European Caucasians, North Americans and Japanese. We undertook the current study to examine whether the STAT4 SNPs are also associated with susceptibility to SSc and SSc subsets in a Han Chinese population. A total of 453 Han Chinese patients with SSc and 534 healthy controls were examined in the study. The SNPs rs7574865, rs10168266 and rs3821236 of the STAT4 gene were examined with SNP TaqMan assays. The T-allele carriers of rs7574865 and rs10168266 were strongly associated with the presence of anti-topoisomerase I (ATA) and pulmonary fibrosis in SSc patients, as well as with diffuse cutaneous SSc (dcSSc). The presence of anti-centromere (ACA) and limited cutaneous SSc (lcSSc) did not show significant association with any of the examined SNPs. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc. It also revealed different genetic aspects of SSc subsets in a Han Chinese population.

Association ofSTAT4gene polymorphism with increased susceptibility of rheumatoid arthritis in a northern Chinese Han subpopulation

Several studies have reported STAT4 polymorphism is strongly associated with increased susceptibility to rheumatoid arthritis (RA). However, a study from China showed no association between STAT4 and RA susceptibility in a Chinese Han subpopulation. Since the northern Hans are known to be genetically different from the southern Hans, the aim of this study was to investigate the association of STAT4 polymorphism with RA in a large cohort of a northern Chinese Han subpopulation. 640 RA patients and 662 healthy controls were enrolled. DNA samples were genotyped for STAT4 rs7574865 by direct sequencing. The association of single nucleotide polymorphism (SNP) rs7574865 with RA susceptibility was calculated and the relationship between rs7574865 polymorphism and RA subgroups stratified by clinical features was estimated. We confirmed a significant association of STAT4 rs7574865 polymorphism with RA susceptibility in northern Chinese Han population. The frequency of the minor T allele in RA was significantly higher than in healthy controls (35.2% vs. 31.1%; P = 0.029, OR 1.2 [95% CI 1.02-1.41]). There was also a significant difference in the distribution of the genotypes of SNP rs7574865 between RA patients and healthy controls (P = 0.02). Stratification analyses showed no associations between the genetic risk and clinical/serologic features, but a potential high frequency of TT genotype in a rheumatoid factor-negative subgroup, although it did not reach statistical significance (P = 0.084, OR 2.01 [95% CI 0.91-4.45]). STAT4 rs7574865 is significantly associated with RA susceptibility in northern Chinese Han subpopulations. The genetic differences of Han subpopulations should be considered when genetic susceptibility for diseases is studied.

An SduI polymorphism at intron 20 of the Chinese Holstein cow STAT4 gene and its effect on milk performance traits

The signal transducer and activator of transcription (STAT) genes are responsive to a wide range of cytokines, growth factors, and hormones, and thus control important biological processes. In humans, STAT4 mutations have been identified as genetic markers for rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome, whereas little research has been conducted on bovine STAT4 mutations and their potential effects. Herein, 585 Chinese Holstein cows were used to investigate STAT4 mutations and their effects on milk performance traits. One haplotype block, containing g.95879G>A, g.96013G>C, was identified in intron 20 of the bovine STAT4 gene by restriction fragment length polymorphism-polymerase chain reaction and DNA sequencing. Two single nucleotide polymorphisms were significantly associated with milk yield at 305 days (P < 0.05), and with protein percentage (P < 0.05). Chinese Holstein cows with the haplotype GGGG had higher milk yields at 305 days and lower protein percentages. These results suggest that the 2 single nucleotide polymorphisms of STAT4 could be used as genetic markers for milk performance traits in Chinese Holstein cows.

STAT3 Polymorphism Can Predict the Response to Interferon-α Therapy in Patients with Metastatic Renal Cell Carcinoma

BackgroundIn our 2007 retrospective study, we reported that single nucleotide polymorphisms (SNPs) in the signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3) gene were significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC). ObjectiveTo prospectively confirm those results, the Japan Immunotherapy SNPs-Study Group for Kidney Cancer conducted this trial. Design, setting, and participantsIn this multicenter, prospective study, 203 eligible patients were enrolled. We evaluated the correlation between the antitumor effects of IFN-α and 11 SNPs (STAT3-2, STAT3-0, SOCS3-1, IL4R-34, PTGS1-3, PTGS1-4, PTGS1-5, PTGS2-12, IRF2-67, ICSBP-38, and TAP2-5) in eight genes in 180 patients who received IFN-α for >12 wk. InterventionsPatients were treated with three doses per week of IFN-α 5 million IU. Outcome measurements and statistical analysisWe analyzed the association of response to IFN-α and overall survival (OS) with genetic polymorphisms using a chi-square test and a logistic regression model. Results and limitationsThe response rate of IFN-α was 13.8% (28 of 203 patients; 9 complete responses [CRs], 19 partial responses [PRs]). The CR rate of 4.4% was higher than we expected. Response to IFN-α was not associated with any of the 11 SNPs examined. However, when we assessed patients with CR, PR, and stable disease >24 wk as a group representing those with clinical response, a significant association was observed between STAT3-2 (rs1905341) and the clinical response of IFN-α (p=0.039). Namely, C/C genotype of STAT3-2 was significantly associated with the clinical response of IFN-α and OS. These results were generated in Japanese patients and should be studied in other ethnic groups. ConclusionsThis is the first prospective study demonstrating that a STAT3 polymorphism can be a predictive marker for treatment with IFN-α for patients with mRCC.

Variants Within STAT Genes Reveal Association with Anticitrullinated Protein Antibody-negative Rheumatoid Arthritis in 2 European Populations

STAT3 and 4 are, among other factors, critical for the interleukin 12 (IL-12)-mediated Th1 response, for transfer of IL-23 signals, and for survival and expansion of Th17 cells. We investigated the association of STAT3 and STAT4 polymorphisms with serologically distinct subgroups of rheumatoid arthritis (RA). A total of 41 single-nucleotide polymorphisms (SNP) within STAT3 and STAT1-STAT4 loci were investigated in a Swedish cohort of 2043 RA cases and 1115 controls. Nine of the associated SNP were tested in a Spanish cohort of 1223 RA cases and 1090 controls. Fourteen SNP in the STAT3 and STAT1-STAT4 loci were associated with anticitrullinated protein antibody (ACPA)-negative RA in the Swedish cohort. Three of the SNP in STAT4 and 2 SNP in STAT3 remained associated with ACPA-negative RA after considering the Spanish results. In addition, rs7574865 and rs10181656, in STAT4, were associated with ACPA-positive RA in the Swedish study. One of these SNP, rs7574865, showed a similar pattern of the association in serologically distinct subgroups of RA in a metaanalysis of all 7 published studies. Our findings suggest that variants in STAT genes may contribute differentially to susceptibility to RA in seropositive and in seronegative patients.

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children

Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population

AimsAlthough polymorphisms in IL23R have recently been proposed to predispose to Behcet's disease (BD), associations between IL23R polymorphisms and intestinal BD have yet to be elucidated. We therefore performed a study to evaluate whether IL17A, IL23R, and STAT4 polymorphisms are associated with susceptibility to intestinal BD in the Korean population. Main methodsSingle nucleotide polymorphisms (SNP) in the IL17A, IL23R, and STAT4 genes were analyzed using DNA sequencing, denaturing high performance liquid chromatography, and TaqMan genotyping assays. Key findingsIndividual polymorphism analysis revealed that the TT genotype of IL17A rs8193036 (odds ratio (OR) 2.10, 95% confidence interval (CI) (1.12–3.92), p=0.021), and GG+GT genotype of IL23R rs1884444 (OR 1.92, 95% CI (1.03–3.57), p=0.034) was associated with the development of intestinal BD. When these two genotypes were combined, the risk of BD increased compared to that of patients with no-risk or one-risk genotype (OR 2.21, 95% CI (1.13–4.34), p=0.021). Furthermore, statistically significant gene–gene interactions were observed between G149R in IL23R vs. rs11685878 in STAT4, rs2275913 in IL17A vs. rs7574865 in STAT4, and rs11889341 in STAT4 vs. rs2275913 in IL17A. The haplotypes of IL17A had a positive association with intestinal BD risks, whereas those of IL23R were protective for disease development. SignificanceOur results indicate that the interaction of specific IL17A, IL23R, and STAT4 SNPs modulate susceptibility to intestinal BD in the Korean population, suggesting that the IL-17/23 axis plays a significant role in disease pathogenesis.

Association of Polymorphisms of STAT6 and SO2 with Chinese Childhood Asthma: a Case-control Study

ObjectiveTo investigate the association of polymorphisms of STAT6 gene and air pollutants of PM10, NO2, and SO2, with asthma in Chinese children. Methods418 subjects aged 14 years and under were recruited in a case-control study. The association between STAT6 polymorphisms and childhood asthma were tested by allele frequency, genotype analysis, and MDR analysis. Exposure to outdoor air pollutants was estimated by a 5-day moving average level. Statistical analyses were performed with SAS 9.1 software. ResultsOnly 3 alleles of GT repeats at exon 1 of STAT6 were found in Chinese children. C258T and T710C were 2 new SNPs of STAT6 at 3′-UTR. Children who carried T allele of C258T were more common in asthma children than in control subjects (P<0.05). The MDR analysis showed that GT repeats, C258T and T710C of STAT6 polymorphisms interacted together in leading to susceptibility to childhood asthma among Chinese people. After confounding factors were controlled, such as SNP C258T, family history of asthma, frequency of influenza within a year, the 5-day average of SO2 was tested to be a key risk factor of asthma in Chinese children (P<0.05). ConclusionChinese children differed in polymorphisms of STAT6 and in its relation with childhood asthma.

Association of STAT4, IRF5 and BLK polymorphisms with severity and outcome in lupus nephritis

Backgroundand objectivesLupus nephritis (LN) is a cause of significant morbidity and mortality and occurs in 15–50% of patients with SLE. Proliferative nephritis is most severe and 10% of LN patients...

75 STAT3 polymorphism can predict clinical benefits of interferon-α in patients with metastatic renal cell carcinoma

75 STAT3 polymorphism can predict clinical benefits of interferon-α in patients with metastatic renal cell carcinoma

Association of STAT6 and ADAM33 single nucleotide polymorphisms with asthma bronchiale and IgE level and its possible epigenetic background

ADAM33 and STAT6 belong to the candidate genes that have been commonly associated with asthma, bronchial hyperresponsiveness or IgE levels. Our objective was to assess the association of 11 SNPs of the ADAM33 and 6 of the STAT6 and their haplotypes with IgE levels and asthma. We also evaluated the possible role of parental origin of haplotypes on IgE levels. We enrolled 109 children with asthma and 45 healthy controls. Genotyping was performed by TaqMan probes and confirmed by sequencing. Haplotype construction was based on the knowledge of parental genotypes and also inferred by using the EM algorithm and Bayes' theorem. None of the SNPs were associated with elevated IgE level or asthma. We found that the most frequent STAT6 haplotype ATTCAA (built from rs324012, rs324011, rs841718, rs3024974, rs3024974, rs4559 SNPs, respectively) was associated with elevated total IgE levels (P=0.01) and this haplotype was predominantly transmitted paternally (P<0.001). We compared our results with those of studies performed on German and Australian Caucasian populations and found that rs324011, rs3024974 and rs4559 SNPs in STAT6 should have a major effect on IgE levels. Therefore, we suggest the TCA haplotype alone (built from rs324011, rs3024974 and rs4559 SNPs, respectively) in STAT6 is associated with total IgE elevation. The influence of paternal origin of the STAT6 haplotype on IgE levels is surprising but the exact role of possible paternal imprinting in STAT6 regulation should be investigated and confirmed in future studies.

Investigation of JAK2, STAT3 and CCR6 polymorphisms and their gene–gene interactions in inflammatory bowel disease

Genome-wide association studies identified many loci associated with the two forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). Components of the interleukin-23 signalling pathway, such as IL23R, JAK2 and STAT3, have been implicated in both diseases. In addition, emerging evidence supports the role of IL23-driven Th17 cells in inflammation. Here, we studied the susceptibility nature of three components of IL23 signalling and Th17 cell differentiation: JAK2 rs10758669, STAT3 rs744166 and CCR6 rs2301436 initially associated with CD in Hungarian CD and UC patients. A total of 616 unrelated subjects with either form of IBD and 496 healthy controls were genotyped with PCR-RFLP methods. We also tested the genetic interactions of JAK2, STAT3 and CCR6 polymorphisms in a pairwise fashion with regard to disease risk. We could confirm the susceptibility of STAT3 rs744166 TT homozygotes for UC (OR: 1.483, 95% CI: 1.103-1.992, P = 0.009). Data on genetic interaction reveals that the above JAK2 and STAT3 risk alleles contribute to CD susceptibility in combination with each other (OR: 2.218; 95% CI: 1.097-4.487; P = 0.024), while the JAK2 variant shows a tendency to confer UC risk only on a wild-type STAT3 background (OR: 1.997, 95%CI: 0.994-4.009, P = 0.049). Our results may help in understanding how these natural variants contribute to development of IBD through their genetic association.

Independent replication of STAT3 association with multiple sclerosis risk in a large German case–control sample

Recent genome-wide association studies have implicated the "signal transducer and activator of transcription 3" gene (STAT3) as a putative new multiple sclerosis (MS) susceptibility locus. However, independent validation studies are sparse. Therefore, we performed a genetic association study of two STAT3 polymorphisms (rs744166 and rs2293152) in a large and independent German case-control sample of 5,904 subjects. We observed a nominally significant, albeit weak association between rs744166 and MS susceptibility (odds ratio = 1.09, P = 0.012) in our sample. This study supports the association between STAT3 and an increase in MS risk. Taking into account the functional role of STAT3, our results favour an involvement of T(h)17 lymphocytes in MS.

Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population

Recently, the association of a common STAT4 haplotype with type 1 diabetes (T1D) as well as rheumatoid arthritis has been documented in Caucasians and Koreans. STAT4 is involved in the signalling of interleukin-12 and γIFN, as well as interleukin-23. To discover genes affecting the susceptibility of common autoimmune diseases, we studied the association of polymorphisms in STAT4 with autoimmune thyroid disease (AITD) as well as T1D in the Korean population. Four single-nucleotide polymorphisms on the chromosome 2q (rs11889341, rs7574865, rs8179673, and rs10181656), which were found to associate with rheumatoid arthritis were examined for association in a Korean sample of 428 AITD, 418 T1D patients, and 1060 controls. The minor alleles of all four single-nucleotide polymorphisms and the reconstructed STAT4 haplotypes conferred significant degree of risk for AITD (p=10(-2) to 10(-4)). Although we found a weak association of rs11889341 with T1D (p<0.05), the same haplotypes were not associated with T1D susceptibility. When we stratified T1D patients according to the age of onset, the minor alleles of all four single-nucleotide polymorphisms and the same haplotypes showed significant association with the susceptibility of T1D in the early-onset subgroup (p<0.01), not in the late-onset subgroup. STAT4 alleles and the same haplotypes might influence cytokine signalling, and therefore the development of AITD as well as T1D. These results reinforce the influence of STAT4 gene as a general autoimmune gene.

TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey

A significant source of variability in the literature on systemic lupus erythematosus (SLE) susceptibility genes has been the inability to replicate genetic findings across different racial or ethnic groups. We investigated whether a single nucleotide polymorphism (SNP) of the STAT4 (rs7574865), PTPN22 (rs2476601), TRAF1/C5 (rs10818488), and C1q (rs292001) genes as well as the 27-bp VNTR polymorphism on intron 4 of eNOS, previously associated with SLE in other populations, are also associated with SLE risk in Turkey. A group of 158 SLE patients and 155 healthy controls were included in this study. A genetic association of the TRAF1/C5, C1q, and eNOS gene polymorphism, but not of STAT4 and PTPN22, was found to confer a degree of risk for SLE. These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations.

Association of STAT4 polymorphisms with susceptibility to primary membranous glomerulonephritis and renal failure

Background Membranous glomerulonephritis (MGN) is one of common causes of idiopathic nephrotic syndrome in adults, and 25% of MGN patients proceed to end-stage renal disease. STAT4 gene polymorphisms have been reported to be associated with many inflammatory diseases. The objective of this study was to clarify the relationship between STAT4 gene polymorphisms and the pathogenesis of MGN. Methods We investigated the association of three STAT4 gene polymorphisms (rs3024912, rs3024908, and rs3024877) with the susceptibility to MGN in 403 Taiwanese populations (138 MGN patients and 265 controls). Results The results indicated that the statistically significant difference in genotype frequency distribution was found at rs3024908 SNP in MGN patients and control groups ( p = 0.014). In addition, the individuals with the GG genotype at rs3024912 SNP may have a higher risk in kidney failure of MGN patients (adjusted odds ratio [OR] = 3.255; 95% confidence interval [CI] = 1.155–9.176, p = 0.026). Conclusions Our data provide a new information that the STAT4 (rs3024912 and rs3024908) polymorphisms may be the underlying cause of MGN, and these polymorphisms revealed by this study warrant further investigation.

STAT3 gene polymorphisms and susceptibility to non-small cell lung cancer

Signal transducer and activator of transcription protein 3 (STAT3) has been implicated in cancer development and is recognized as a type of oncogene. However, association studies of single nucleotide polymorphisms (SNPs) in the STAT3 gene with cancer risk are rare and not available for lung cancer. We examined whether STAT3 polymorphisms are associated with the risk of non-small cell lung cancer (NSCLC). Eight SNPs in the STAT3 gene were genotyped by TaqMan assays in 326 NSCLC cases and 432 controls in a Chinese population. Significant decreased risk of NSCLC was observed for carriers of minor alleles rs4796793 (odds ratio (OR) = 0.68, 95% confidence interval (CI) = 0.51-0.92), rs7211777 (OR = 0.67, 95%CI = 0.50-0.90), rs12949918 (OR = 0.73, 95%CI = 0.54-0.97), rs744166 (OR = 0.69, 95%CI = 0.51-0.92), rs9912773 (OR = 0.75, 95%CI = 0.55-0.98), and rs3869550 (OR = 0.70, 95%CI = 0.53-0.94). The GGCGGC haplotype, comprised of minor alleles of the six NSCLC-associated SNPs, had a 0.78-fold (95%CI = 0.62-0.97) significantly decreased risk of NSCLC, as compared to the most common haplotype of CATACT. Stratification analyses by clinical stage showed that the trend for the association between STAT3 polymorphisms and NSCLC risk was present both for stage I/II and stage III/IV, and appeared moderately stronger for stage III/IV. We conclude that polymorphisms in the STAT3 gene may have a protective role in the development of NSCLC, particular of stage III/IV NSCLC.

The Activator of Transcription 3 (STAT3) Gene Polymorphisms Are Associated with Treatment Outcomes In Acute Myeloid Leukemia

AbstractAbstract 4858 Objectives:In the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway signaling pathway, the STAT3 is one of the most prominent predictable factors for cancer and leukemia. STAT3 activation might promote cellular transformation and therefore have an important role in human tumors. This study was aimed to investigate the relationship between the STAT3 polymorphisms and the treatment responses of AML in the Chinese population. Methods:We tested three single nucleotide polymorphisms (SNPs) with 130 Acute Myeloid Leukemia (AML) patients. Genomic DNA was isolated from peripheral blood and assayed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF). Results:The results showed there were strong relationship between unfavorable cytogenetic, partial remission (even no remission) and the frequencies of GG genotype in rs9909659 (P=0.01 and 0.03) and the patients less than 45 years old was significant association with GA/AA genotype (P=0.01). But associations were not confirmed about event-free survival and leukemia-free survival in the Chinese population studied. Conclusions:It is clear that the AML patients with GG genotype in rs9909659 are not sensitive to standard chemotherapy method Disclosures:No relevant conflicts of interest to declare.

Association of STAT3 and TNFRSF1A with ankylosing spondylitis in Han Chinese

ObjectivesRecent association studies by the Australo-Anglo-American Spondyloarthritis Consortium (TASC) in Caucasian European populations from Australia, North America and the UK have identified a number of genes as being associated with...