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

Seddighzadeh, Maria; González, Antonio; Ding, Bo; Ferreiro-Iglesias, Aida; Gómez-Reino, Juan J.; Coordinated,; Klareskog, Lars; Alfredsson, Lars; Dunussi-Joannopoulos, Kyri; Clark, James D.; Padyukov, Leonid

doi:10.3899/jrheum.111284

Cited by 24 publications

(25 citation statements)

References 28 publications

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“…It plays a key role in the IL-12-induced differentiation of T cells into the Th1 pathway and is involved in the production of IL-17 by Th17 cells, in response to IL-23. The current human evidence that STAT4 has been shown to be involved in Th1- or Th17-mediated diseases, and to be associated with a number of autoimmune diseases [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37], indicates that multiple autoimmune diseases share common susceptibility genes, providing a reason to investigate its association with AITD. In this study, we present the first detailed genotype-phenotype analysis of STAT4 gene variants in a large Chinese Han AITD cohort.…”

Section: Resultsmentioning

confidence: 99%

“…Investigating the genetic polymorphism of STAT4 with autoimmune diseases, many recent studies suggested a significant association of STAT4 gene polymorphism with systemic lupus erythematosus (SLE) [19,20,21,22], rheumatoid arthritis (RA) [23,24,25,26], Crohn’s disease [27,28], Sjögren’s disease (SD) [29], systemic sclerosis [30,31], Behcet’s disease [32,33], and type-1 diabetes (T1D) [34,35,36] as well as psoriasis [37], thus indicating common genetic involvement in multiple autoimmune diseases. Until now, there are only limited data including a study reporting a significant association of the STAT4 gene single nucleotide polymorphism (SNP) (rs11889341 and rs7574865) with AITD in the Korean population [34].…”

Section: Introductionmentioning

confidence: 99%

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Association between STAT4 Gene Polymorphisms and Autoimmune Thyroid Diseases in a Chinese Population

Meng

Zhou

et al. 2014

IJMS

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association between STAT4 Gene Polymorphisms and Autoimmune Thyroid Diseases in a Chinese Population

Meng

Zhou

et al. 2014

IJMS

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“…Recent studies have shown increased expression of genes and activation of transcription factors in IL-6/STAT3 pathways in anti-citrullinated peptide antibody (ACPA)-negative RA patients as compared to ACPA- positive patients 910 . Also, polymorphisms in the transcription factor STAT3 are associated with development of RA in seronegative patients to a greater degree than in seropositive patients 11 . Given the upregulation of IL-6/STAT3 signaling, there is a theoretical basis that targeting the IL-6 receptor with the monoclonal antibody, tocilizumab (TCZ), would be more effective in patients with seronegative RA.…”

Section: Introductionmentioning

confidence: 99%

Tocilizumab treatment leads to improvement in disease activity regardless of CCP status in rheumatoid arthritis

Cappelli

Palmer²,

Kremer

et al. 2017

Seminars in Arthritis and Rheumatism

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Objective Autoantibodies can be useful in predicting response to certain treatments in rheumatoid arthritis (RA). We aimed to evaluate initial response to tocilizumab (TCZ) by change in physician and patient reported outcomes and laboratory parameters in a real world cohort of patients with RA. We analyzed data by autoantibody status to determine whether patients with seronegative RA had improved response to tocilizumab when compared to their seropositive counterparts. Methods Data from the CORRONA RA registry was analyzed. Patients were included if they were started on TCZ and had data from a follow up visit 4-8 months after initiation, as well as having information on serologic status. Serologic status was determined by presence of anti-cyclic citrullinated peptide (CCP) antibodies. Changes in disease activity measures from baseline to follow up visit were evaluated. Results Both CCP negative and positive groups had statistically significant improvement in physician reported measurements (physician rating of disease activity, joint counts), patient reported measures (disease activity, pain, fatigue), and acute phase reactants after 4-8 months of treatment with tocilizumab. The magnitude of improvement, however, did not differ significantly by CCP status. Conclusion Tocilizumab led to statistically significant improvement in all patient and physician reported measures of disease activity evaluated in this cohort of patient with RA. The response to tocilizumab did not differ by CCP status.

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“…Moreover, in a study with Japanese patients, there was a significant association between SLE and STAT4 but not STAT1 SNP genotypes [32]. Furthermore, there was confirmed association of STAT3 and STAT4 SNP genotypes to rheumatoid arthritis, which was shown by two studies with European patients [21].…”

Section: Discussionmentioning

confidence: 83%

“…Three SNPs were chosen -rs10208033 (C/T), rs12693591 (A/C), and rs1467199(C/G) -to represent the STAT1 gene loci for genotyping. SNP rs12693591 is located in the intron region of the STAT1 gene; it is implicated in anticitrullinated protein antibody (ACPA)-negative rheumatoid arthritis (RA) [21]. SNPs rs1467199 and rs10208033 are located in the promoter region of the STAT1 gene at the transcription factor binding sites.…”

Section: Genotyped Of Three Snps In Stat1 Gene By Sequenom Massarraymentioning

confidence: 99%

STAT1 single nucleotide polymorphisms and susceptibility to immune thrombocytopenia

Chen

Guo

et al. 2015

Autoimmunity

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Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. One of the key mediators of IFN-γ signaling is the signal transducer and activator of transcription 1 protein (STAT1). We evaluated the relationship between STAT1 gene single nucleotide polymorphisms (SNPs) and the associated risk of ITP in a prospective case-control study. A total of 548 children were recruited: 328 children with ITP and 220 healthy children as sex- and age-matched normal controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect three SNPs genotypes in the STAT1 gene: rs10208033, rs12693591, and rs1467199. There is a statistically significant difference in STAT1 rs1467199 allele frequencies with comparison of each of the four clinical subgroups of ITP patients to the normal controls (p = 0.0432). Also, newly diagnosed ITP patients and chronic ITP patients demonstrate significant different genotypes (χ(2 )= 8.511, p = 0.0142) and allelic frequency (p = 0.0055). Although a positive STAT1 rs1467199 genotype subgroups to the STAT1 mRNA expression level cannot be established, there is a weak correlation between STAT1 mRNA level and the activity ratio of Type 1 T helper lymphocyte and Type 2 T helper lymphocyte (Th1/Th2 ratio) (p = 0.0544); correlation with IFN-γ alone did not reach statistical significance (p = 0.1715). The findings in our study suggest that STAT1 rs1467199 SNP plays a potential role in the IFN-γ dependent development of autoimmunity in children with ITP. The important clinical implication of STAT1 SNPs testing as a predictor of pediatric chronic ITP will be validated in future molecular and protein functional analysis.

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

Abstract: Our findings suggest that variants in STAT genes may contribute differentially to susceptibility to RA in seropositive and in seronegative patients.

Cited by 24 publications

References 28 publications

Association between STAT4 Gene Polymorphisms and Autoimmune Thyroid Diseases in a Chinese Population

Association between STAT4 Gene Polymorphisms and Autoimmune Thyroid Diseases in a Chinese Population

Tocilizumab treatment leads to improvement in disease activity regardless of CCP status in rheumatoid arthritis

STAT1 single nucleotide polymorphisms and susceptibility to immune thrombocytopenia

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