title: The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and influences its erosive phenotype.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: GenHotel-EA 3886, University Evry-Paris 7 Medical School, Member of the AutoCure European Consortium, Evry-Genopole cedex, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Dawidowicz
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guedj
authors.forename: Céline
authors.initials: C
authors.lastname: Pierlot
authors.forename: Stefano
authors.initials: S
authors.lastname: Bombardieri
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.forename: René
authors.initials: R
authors.lastname: Westhovens
authors.forename: Pilar
authors.initials: P
authors.lastname: Barrera
authors.forename: Helena
authors.initials: H
authors.lastname: Alves
authors.forename: Vitor Hugo
authors.initials: VH
authors.lastname: Teixeira
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petit-Teixeira
authors.forename: Leo
authors.initials: L
authors.lastname: van de Putte
authors.forename: Piet
authors.initials: P
authors.lastname: van Riel
authors.forename: Bernard
authors.initials: B
authors.lastname: Prum
authors.forename: Thomas
authors.initials: T
authors.lastname: Bardin
authors.forename: Olivier
authors.initials: O
authors.lastname: Meyer
authors.forename: François
authors.initials: F
authors.lastname: Cornélis
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012217:Rheumatoid Factor / Q000097:blood; D055815:Young Adult
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D012217:Rheumatoid Factor