Association of a functional polymorphism in the <i>IRF5</i> region with systemic sclerosis in a Japanese population

Ito, Ichiaki; Kawaguchi, Yasushi; Kawasaki, Aya; Hasegawa, Minoru; Ohashi, Jun; Hikami, Koki; Kawamoto, Manabu; Fujimoto, Manabu; Takehara, Kazuhiko; Sato, Shinichi; Hara, Masako; Tsuchiya, Naoyuki

doi:10.1002/art.24600

Cited by 116 publications

(63 citation statements)

References 15 publications

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“…The interferon regulatory factor 5 (IRF5) is a transcription factor that mediates activation of interferon and the immune system (1,2). Recently, an association ofthe IRF5 polymorphism with SSc was reported in Caucasians populations of Europe and North America, as well as in Japanese populations (3)(4)(5)(6). However, genetic heterogeneity in different ethnic populations may significantly impact the complex trait of SSc and SSc clinical features.…”

Section: Received September 10 2014 -Accepted October 10 2014mentioning

confidence: 99%

Association of the IRF5 SNP rs2004640 with Systemic Sclerosis in Han Chinese

Wang

Yao

Guo³

et al. 2014

Int J Immunopathol Pharmacol

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Systemic sclerosis (SSc) is a complex disease involving multiple genetic factors. An association of the IRF5 polymorphism with SSc was reported in Caucasian populations of Europe and North America, as well as in Japanese populations. The present study aimed to examine whether the SSc-associated SNP rs2004640 of IRF5 gene confer susceptibility to SSc and clinical features of SSc in a Han Chinese population. A Han Chinese cohort consisting of 424 SSc patients and 502 healthy controls were examined in the study. TaqMan assays were carried out to examine the SNP. Exact p-values were obtained (Fisher's test) from 2×2 tables of allele counts and disease status. SSc patients of Han Chinese showed increased homozygous TT genotype of the rs2004640 (p = 0.027, odds ratio (OR) = 1.4, CI =1.03–1.93), which was significantly associated with pulmonary fibrosis of SSc and ATA-positive SSc of Han Chinese. The lcSSc and ACA-positive SSc of Han Chinese appeared also in association with the increased T allele frequency. However, the Chinese dcSSc did not show any association with the rs2004640. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of IRF5 may play an important role in susceptibility to SSc.

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Section: Received September 10 2014 -Accepted October 10 2014mentioning

confidence: 99%

Association of the IRF5 SNP rs2004640 with Systemic Sclerosis in Han Chinese

Wang

Yao

Guo³

et al. 2014

Int J Immunopathol Pharmacol

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“…Although how the TLR4 signaling pathway contributes to SSc pathogenesis remains enigmatic, it is interesting that several independent case-control and genome-wide association studies identify IFN regulatory factor 5 (IRF5), a member of the IFN regulatory factor (IRF) family, as an SSc susceptibility gene (10)(11)(12)(13)(14)(15). IRFs were identified primarily in the research of the type I IFN system and have been shown to have functionally diverse roles in the regulation of the innate and adaptive immune responses (16).…”

mentioning

confidence: 99%

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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“…As in the case of SLE, polymorphisms in the genes encoding proteins involved in the activation or activity of type I IFNs are also associated with a predisposition to develop certain of these diseases. For example, polymorphisms in the STAT4 and IRF5 genes are associated with an increased risk of developing systemic sclerosis, an autoimmune connective tissue disorder characterized by fibrosis of multiple organs and a type I IFN signature [Dieude et al 2009;Ito et al 2009;Rueda et al 2009]. …”

Section: Therapeutic Advances In Drug Safety 2 (3)mentioning

confidence: 99%

“…Given the key role played by type I IFNs in the innate immune response it is perhaps not surprising that dysregulation of the type I IFN pathway can under certain circumstances lead to induction or exacerbation of autoimmune disease in predisposed individuals [Burdick et al 2009]. Thus, polymorphisms in the genes encoding key intermediates in the type I IFN pathway have been identified as risk factors for the development of autoimmune disease [Dieude et al 2009;Ito et al 2009;Rueda et al 2009], and a number of IFN-induced proteins are up regulated in active disease [Ronnblom et al 2006;Baechler et al 2003]. Furthermore, a recent report has shown that a loss of function variant in the gene encoding MAVS, a key antiviral molecule downstream of the cytosolic doublestranded RNA sensors RIG-I and MDA-5, is associated with low type I IFN production and the absence of anti-RNA-binding protein autoantibodies in a novel subphenotype of SLE [Pothlichet et al 2011].…”

Section: Adverse Events: Underlying Mechanisms and Clinical Implicationsmentioning

confidence: 99%

Immunogenicity and other problems associated with the use of biopharmaceuticals

Tovey¹,

Lallemand

2011

Therapeutic Advances in Drug Safety

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Biopharmaceuticals are used widely for the treatment of cancer, chronic viral hepatitis, inflammatory, and autoimmune diseases. Biopharmaceuticals such as interferons are well tolerated for the most part with the most common adverse events observed being 'flu-like' symptoms that resolve rapidly after initial treatment. Prolonged treatment is associated, however, with more serious adverse events including leucopenia, thrombocytopenia, and neuropsychiatric effects, which may necessitate dose reduction or even cessation of treatment in some patients. Recombinant growth factors, such as erythropoietin (EPO), granulocyte colony-stimulating factor, or granulocyte macrophage colony-stimulating factor, are for the most part well tolerated, although severe complications have been reported in patients with cancer or chronic kidney disease treated with EPO. Similarly, treatment of patients with cancer with high doses of interleukin-2 is associated with significant toxicity. Treatment of chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and Crohn's disease, with antitumor necrosis factor-alpha monoclonal antibodies is associated with an increased risk of granulomatous infections and, in particular, tuberculosis. The monoclonal antibody, natalizumab, that targets alpha4 integrins is effective in the treatment of multiple sclerosis but is associated with the activation of JC virus and development of progressive multifocal leukoencephalopathy. Repeated administration of recombinant proteins can cause a break in immune tolerance in some patients resulting in the production of a polyclonal antibody response that can adversely affect pharmacokinetics and clinical response. In addition, neutralizing antibodies that cross react with nonredundant essential proteins such as EPO can cause severe autoimmune reactions.

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Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population

Cited by 116 publications

References 15 publications

Association of the IRF5 SNP rs2004640 with Systemic Sclerosis in Han Chinese

Association of the IRF5 SNP rs2004640 with Systemic Sclerosis in Han Chinese

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

Immunogenicity and other problems associated with the use of biopharmaceuticals

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