ArticleArthritis and rheumatism2009
Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines.
Article in Arthritis and rheumatism, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 4 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
56 citing papers in PubMed, 4 syntheses or guidelines pooled it, 105 citations in OpenAlex.
- T-bet: biological functions, molecular mechanisms, and therapeutic applications: a systematic review.Frontiers in immunology · 2026Pooled it
- Unfolding the pathogenesis of scleroderma through genomics and epigenomics.Journal of autoimmunity · 2017Pooled it
- Identification of an Association of TNFAIP3 Polymorphisms With Matrix Metalloproteinase Expression in Fibroblasts in an Integrative Study of Systemic Sclerosis-Associated Genetic and Environmental Factors.Arthritis & rheumatology (Hoboken, N.J.) · 2016Pooled it
- Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis.Molecular biology reports · 2012Pooled it
- Recent Advances in Biomarkers of Systemic Sclerosis-Associated Interstitial Lung Disease: Clinical Relevance and Therapeutic Perspectives.Life (Basel, Switzerland) · 2026Review
- Lack of association of the PLD4 SNP rs2841277 with systemic sclerosis in a European American population.Scientific reports · 2024Article
- Immunogenetics of Systemic Sclerosis.Genes · 2024Review
- Article
- STAT4 gene polymorphisms in human diseases.Frontiers in immunology · 2024Review
- TBX21, the Master regulator of the type 1 immune response, overexpresses in the leukocytes of peripheral blood in patients with late-onset Alzheimer's disease.Immunity & ageing : I & A · 2023Article
- Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response.The Journal of rheumatology · 2023Review
- Type I Interferons in Autoimmunity.The Journal of investigative dermatology · 2022Review
- Combined Analysis of RRBS DNA Methylome and Transcriptome Reveal Novel Candidate Genes Related to PorcineFrontiers in genetics · 2022Article
- Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights.Frontiers in pharmacology · 2022Review
- Updates on genetics in systemic sclerosis.Inflammation and regeneration · 2021Review
- Molecular "omic" signatures in systemic sclerosis.European journal of rheumatology · 2020Review
- Novel insights into dendritic cells in the pathogenesis of systemic sclerosis.Clinical and experimental immunology · 2020Review
- Genetic Susceptibility to Systemic Sclerosis in the Greek-Cypriot Population: A Pilot Study.Genetic testing and molecular biomarkers · 2020Article
- Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.Frontiers in genetics · 2020Article
- Evolving insights into the cellular and molecular pathogenesis of fibrosis in systemic sclerosis.Translational research : the journal of laboratory and clinical medicine · 2019Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
objectiveSystemic 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.
methodsWe 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.
resultsMultiple 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.
conclusionThe 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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Registered trials
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