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Polymorphisms of the STAT4 gene in the pathogenesis of tuberculosis.

ABSTRACT: The signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor that transmits signals induced by several cytokines which play critical roles in the development of autoimmune and chronic inflammatory diseases. In the present study, we have investigated the association between STAT4 polymorphisms and a predisposition to Mycobacterium tuberculosis (MTB) infection and pulmonary tuberculosis (PTB). In the present study, a total of 209 cases of PTB, 201 subjects with latent TB infection (LTBI), and 204 healthy controls (HC) were included. Logistic regression analyses were used to calculate P-values, odds ratios (ORs), and 95% confidence intervals (CIs) for assessing the association between single nucleotide polymorphisms (SNPs) and disease risk. We used Bonferroni correction to adjust the P-values. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. For the rs7574865 polymorphism, the GT genotype is less frequent in the LTBI group compared with HC (P=0.028, OR = 0.62; 95%CI: 0.40-0.95). In addition, the prevalence of the rs897200 CC genotype was lower in the PTB cases compared with LTBI individuals (P=0.039, OR = 0.54; 95%CI: 0.30-0.97). However, no SNPs within STAT4 were associated with PTB or LTBI after Bonferroni correction. Our study demonstrated that STAT4 variants were not related to LTBI and PTB.

SUBMITTER: Wu S

PROVIDER: S-EPMC6131199 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Polymorphisms of the STAT4 gene in the pathogenesis of tuberculosis.

Wu Shouquan S Wang Minggui M Wang Yu Y Zhang Miaomiao M He Jian-Qing JQ

Bioscience reports 20180829 4

The signal transducer and activator of transcription 4 (STAT4) gene encodes a transcription factor that transmits signals induced by several cytokines which play critical roles in the development of autoimmune and chronic inflammatory diseases. In the present study, we have investigated the association between STAT4 polymorphisms and a predisposition to Mycobacterium tuberculosis (MTB) infection and pulmonary tuberculosis (PTB). In the present study, a total of 209 cases of ...[more]

PMID: 30054428

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Project description:INTRODUCTION: Recent studies identified STAT4 (signal transducers and activators of transcription-4) as a susceptibility gene for systemic lupus erythematosus (SLE). STAT1 is encoded adjacently to STAT4 on 2q32.2-q32.3, upregulated in peripheral blood mononuclear cells from SLE patients, and functionally relevant to SLE. This study was conducted to test whether STAT4 is associated with SLE in a Japanese population also, to identify the risk haplotype, and to examine the potential genetic contribution of STAT1. To accomplish these aims, we carried out a comprehensive association analysis of 52 tag single nucleotide polymorphisms (SNPs) encompassing the STAT1-STAT4 region. METHODS: In the first screening, 52 tag SNPs were selected based on HapMap Phase II JPT (Japanese in Tokyo, Japan) data, and case-control association analysis was carried out on 105 Japanese female patients with SLE and 102 female controls. For associated SNPs, additional cases and controls were genotyped and association was analyzed using 308 SLE patients and 306 controls. Estimation of haplotype frequencies and an association study using the permutation test were performed with Haploview version 4.0 software. Population attributable risk percentage was estimated to compare the epidemiological significance of the risk genotype among populations. RESULTS: In the first screening, rs7574865, rs11889341, and rs10168266 in STAT4 were most significantly associated (P < 0.01). Significant association was not observed for STAT1. Subsequent association studies of the three SNPs using 308 SLE patients and 306 controls confirmed a strong association of the rs7574865T allele (SLE patients: 46.3%, controls: 33.5%, P = 4.9 x 10(-6), odds ratio 1.71) as well as TTT haplotype (rs10168266/rs11889341/rs7574865) (P = 1.5 x 10(-6)). The association was stronger in subgroups of SLE with nephritis and anti-double-stranded DNA antibodies. Population attributable risk percentage was estimated to be higher in the Japanese population (40.2%) than in Americans of European descent (19.5%). CONCLUSIONS: The same STAT4 risk allele is associated with SLE in Caucasian and Japanese populations. Evidence for a role of STAT1 in genetic susceptibility to SLE was not detected. The contribution of STAT4 for the genetic background of SLE may be greater in the Japanese population than in Americans of European descent.

Project description:OBJECTIVE:Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. Dysregulation of the immune system, including the Th1/Th2 cytokine balance, is central to the pathogenesis of SSc. This study was undertaken to investigate the hypothesis that single-nucleotide polymorphisms (SNPs) in TBX21 and STAT4, both of which are critical transcription factors that regulate the Th1/Th2 balance, are associated with SSc susceptibility. METHODS:We tested SNPs in TBX21 and STAT4 for association with SSc in 2 independent cohorts, the SSc Registry cohort (880 SSc cases and 507 controls) and the University of Texas SSc cohort (522 cases and 531 controls). Additional white control genotypes were obtained from public repositories. We also investigated for gene-gene interactions. Plasma cytokines and whole blood gene expression profiles were examined to determine functional effects of these SNPs. RESULTS:Multiple SNPs in TBX21 and STAT4 were found to be associated with SSc. In a combined analysis of 902 SSc patients and 4,745 controls, TT genotyping of the TBX21 rs11650354 variant revealed a recessive pattern for disease susceptibility (Pcorr=1.4x10(-15), odds ratio 3.37, 95% confidence interval 2.4-4.6). In an analysis of 1,039 SSc patients and 3,322 controls, the A allele of the STAT4 variant rs11889341 was associated with increased SSc susceptibility in a dominant pattern (Pcorr=2.4x10(-5), odds ratio 1.29, 95% confidence interval 1.2-1.5). Furthermore, we identified gene-gene interaction among the TBX21 and STAT4 variants, such that the STAT4 genotype increased the risk of SSc only in the TBX21 CC genotype group. SSc patients carrying the TBX21 CC genotype had higher interleukin-6 (IL-6) and tumor necrosis factor alpha levels, and those with the TT genotype had elevated IL-2, IL-5, IL-4, and IL-13 (Th2) levels, compared with controls. Whole blood expression profiles revealed dysregulation of type I interferon pathways in the CC group and T cell pathways in the TT group of the TBX21 SNP. CONCLUSION:The present results, from studies of 2 independent cohorts, indicate that SNPs in TBX21 and STAT4 contribute uniquely and interactively to SSc susceptibility, leading to altered cytokine balance and immune dysregulation.

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Polymorphisms of the STAT4 gene in the pathogenesis of tuberculosis.

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Polymorphisms of the <i>STAT4</i> gene in the pathogenesis of tuberculosis.

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