Background Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors.
Objective As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype–phenotype analysis.
Methods 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP).
Results Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype ‘R’ (transmission (T)=60.6%, p=23.1×10−5) and the AGG protective haplotype ‘P’ (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10−5 and T=19.6%, p=3.66×10−5, respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10−4, OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively.
Conclusion This study provides the ‘association and linkage proof’ establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.
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Funding This work was supported by Association Française des Polyarthritiques, Société Française de Rhumatologie, Association Rhumatisme et Travail, Foundation for Science and Technology, Portugal (grant SFRH/BD/23304/2005), Association Polyarctique, Groupe Taitbout, Académie Nationale de Médecine, Association de Recherche sur la Polyarthrite, Genopole, Conseil Régional Ile de France, Fondation pour la Recherche Médicale, Université Evry-Val d'Essonne and unrestricted institutional support from Wyeth, Schering-Plough, Pfizer and Amgen. The European Consortium on Rheumatoid Arthritis Families (ECRAF) was initiated with funding from the European Commission (BIOMED2) by: T Bardin, D Charron, F Cornélis (coordinator), S Fauré, D Kuntz, M Martinez, J F Prudhomme, J Weissenbach (France); R Westhovens, J Dequeker (Belgium); A Balsa, D Pascuale-Salcedo (Spain); M Spyropoulou, C Stavropoulos (Greece); P Migliorini, S Bombardieri (Italy); P Barrera, L Van de Putte (The Netherlands); H Alves, A Lopez-Vaz (Portugal).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the CPPRB Kremlin Bicêtre Hospital, AP-HP.
Provenance and peer review Not commissioned; externally peer reviewed.