Analysis of <i>IRF5</i> gene functional polymorphisms in rheumatoid arthritis

Rueda, Blanca; Reddy, M.V. Prasad Linga; González-Gay, Miguel Á.; Balsa, Alejandro; Pascual‐Salcedo, Dora; Petersson, Ingemar F; Eimon, Alicia; Paira, Sergio; Scherbarth, Hugo R.; Pons-Estel, Bernardo A.; González‐Escribano, María Francisca; Alarcón‐Riquelme, Marta E.; Martín, Javier

doi:10.1002/art.22271

Cited by 52 publications

(34 citation statements)

References 15 publications

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“…Patients carrying the IRF5 is a gene implicated in type I IFN secretion after stimulation of innate immunity and in type I IFN signal transduction. A polymorphism located in the splicing sequence of exon 1B of IRF5 (rs2004640) has been found to be associated with several autoimmune diseases (5,6,8), including SS (7). The CGGGG insertion/deletion polymorphism, located in the promoter region of the IRF5 transcript containing exon 1A, is in linkage disequilibrium with rs2004640.…”

Section: Discussionmentioning

confidence: 99%

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

Miceli‐Richard

Gestermann

Ittah

et al. 2009

Arthritis & Rheumatism

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Objective. Interferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5-bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjögren's syndrome (SS) and to assess the functional consequences of this polymorphism. Primary Sjögren's syndrome (SS) is characterized by xerostomia and keratoconjunctivitis sicca due to lymphocytic infiltration of salivary and lacrimal glands, with systemic complications involving the joints, skin, lungs, kidneys, and nervous system and an increased risk of lymphoma. The results of recent studies of pathogenic mechanisms in primary SS have supported the notion that the interferon (IFN) pathway plays a role through an IFN signature, both in peripheral blood mononuclear cells (PBMCs) and in salivary glands (1,2). Moreover, plasmacytoid dendritic cells, the professional cells that secrete IFN␣, are present in salivary glands, the target organ of the autoimmune process (2). Similar findings have been reported in systemic lupus erythematosus,

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Section: Discussionmentioning

confidence: 99%

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

Miceli‐Richard

Gestermann

Ittah

et al. 2009

Arthritis & Rheumatism

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“…After submission of this manuscript, reports of 2 studies showing no association between RA and 2 SNPs in the IRF-5 gene were published (47,48). The reasons for this seeming discrepancy could be related to the fact that the sizes of the cohorts used in the present study were larger and, perhaps more importantly, that patients in the present study were stratified according to anti-CCP antibody status.…”

Section: Discussionmentioning

confidence: 99%

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

Sigurðsson¹,

Padyukov²,

Kurreeman³

et al. 2007

Arthritis & Rheumatism

169

125

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Objective. To determine whether genetic variants of the interferon regulatory factor 5 (IRF-5) and Tyk-2 genes are associated with rheumatoid arthritis (RA).Methods. Five single-nucleotide polymorphisms (SNPs) in IRF5 and 3 SNPs in Tyk2 were analyzed in a Swedish cohort of 1,530 patients with RA and 881 controls. A replication study was performed in a Dutch cohort of 387 patients with RA and 181 controls. All patient sera were tested for the presence of autoantibodies against cyclic citrullinated peptides (anti-CCP).Results. Four of the 5 SNPs located in the 5 region of IRF5 were associated with RA, while no association was observed with the Tyk2 SNPs. The minor alleles of 3 of the IRF5 SNPs, which were in linkage disequilibrium and formed a relatively common haplotype with a frequency of ϳ0.33, appeared to confer protection against RA. Although these disease associations were seen in the entire patient group, they were mainly found in RA patients who were negative for anti-CCP. A suggestive association of IRF5 SNPs with anti-CCP-negative RA was also observed in the Dutch cohort.Conclusion. Given the fact that anti-CCPnegative RA differs from anti-CCP-positive RA with respect to genetic and environmental risk factor profiles, our results indicate that genetic variants of IRF5 contribute to a unique disease etiology and pathogenesis in anti-CCP-negative RA.The type I interferons (IFNs) comprise a large family of cytokines that are typically produced during viral infections, mainly by plasmacytoid dendritic cells (1). In addition to direct antiviral effects, type I IFNs have many important immunomodulatory functions (1). For instance, they cause maturation of dendritic cells, promote T cell activation, and stimulate B cell development and production of antibodies. Data from previous studies indicate that the type I IFN system plays a pivotal role when self tolerance is broken and autoimmune reactions develop (2). Accordingly, the type I IFN system is activated in many autoimmune diseases, including systemic lupus erythematosus (SLE) (2), priDr. Sigurdsson

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“…6 The IRF5 gene was originally found to be associated with systemic lupus erythematosus susceptibility. 7 More recently, other autoimmune diseases such as rheumatoid arthritis, 8 inflammatory bowel disease 9 or Sjö gren's syndrome 10 have been shown to share this genetic risk factor and this finding was corroborated in non-Caucasic populations as well. 11 In multiple sclerosis (MS), two single nucleotide polymorphisms (SNPs) in the IRF5 gene (rs4728142 and rs3807306) reached significant association in the three independent cohorts tested.…”

Section: Introductionmentioning

confidence: 81%

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

et al. 2010

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In recent reports, IRF5 polymorphisms showed significant association with multiple sclerosis (MS) susceptibility in three studied populations and Irf5-deficient mice exhibited an increased susceptibility to viral infection, linked to a significant decrease in the induction of serum type I interferon (IFN). In the present study, we evaluated the association of two IRF5 polymorphisms with MS predisposition and we also addressed whether these polymorphisms were associated with active replication of human herpes virus-6 (HHV-6) observed in a subgroup of MS patients, and/or with response to IFN-b therapy. A total of 1494 MS patients and 1506 ethnically matched controls were genotyped for rs4728142 and rs3807306 with TaqMan pre-designed assays. One hundred and six patients were classified as responders to IFN-b therapy (no relapses/increases in EDSS over the 2-year follow-up) and 112 as non-responders (at least two relapses or an increase in expanded disability status scale (EDSS) of at least one point during the same period). The combined analysis of available datasets yielded an effect size on MS with odds ratio (OR) MantelÀHaenszel ¼ 1.14 (Po0.002) for the IRF5 polymorphisms rs4728142 and rs3807306. Additionally, trends for association were observed between rs3807306T and infection with HHV-6 [p ¼ 0.05, OR (95% CI) ¼ 1.56 (1.00-2.44)] and response to IFN-b therapy [P ¼ 0.09, OR (95% CI) ¼ 1.39 (0.95-2.05)].

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Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis

Cited by 52 publications

References 15 publications

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

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