title: Interferon regulatory factor 5 gene polymorphism confers risk to several rheumatic diseases and correlates with expression of alternative thymic transcripts.
abstract: OBJECTIVE
  Polymorphisms in genes related to the IFN pathway were investigated for susceptibility to rheumatic diseases and correlation with gene expression in thymus.
  
  
  METHODS
  Forty-five polymorphisms were genotyped in Norwegian patients with RA (n = 518), JIA (n = 440), SLE (n = 154) and healthy controls (n = 756). Forty-two thymic samples were used for gene expression analysis. Six hundred and fifty SLE patients and 737 healthy controls from Spain were available for replication.
  
  
  RESULTS
  We found a novel association between interferon regulatory factor 5 (IRF5), rs2004640 and JIA, in particular with the polyarthritis RF-negative patients [odds ratio (OR) = 1.60; 95% confidence interval (CI) 1.17, 2.20; P = 0.003]. Also, we confirmed the associations between rs2004640 and SLE (OR = 1.95; 95% CI 1.50, 2.53; P = 3.75 × 10(-7)), which was further strengthened in a meta-analysis (OR = 1.44; 95% CI 1.36, 1.52; P = 2.11 × 10(-37)). Suggestive evidence of association between rs2004640 and RA was found in the Norwegian discovery cohort (OR = 1.19; 95% CI 1.02, 1.40; P = 0.029) and strengthened in a meta-analysis (OR = 1.11; 95% CI 1.05, 1.18; P = 0.00028). Expression levels of exon 1B IRF5 transcripts were dependent on the presence of the rs2004640 T risk allele in thymic tissue, while exon 1A transcript levels correlated with IRF5 promoter CGGGG-indel variants.
  
  
  CONCLUSIONS
  The IFN pathway gene, IRF5, is a common susceptibility factor for several rheumatic and autoimmune diseases, and risk variants are correlated with expression of alternative IRF5 transcripts in thymus implying a regulatory role.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Ullevål, Kirkeveien 166, N-0407 Oslo, Norway. g.b.namlos@medisin.uio.no
authors.forename: Gry B N
authors.initials: GB
authors.lastname: Nordang
authors.forename: Marte K
authors.initials: MK
authors.lastname: Viken
authors.forename: Silja S
authors.initials: SS
authors.lastname: Amundsen
authors.forename: Elena S
authors.initials: ES
authors.lastname: Sanchez
authors.forename: Berit
authors.initials: B
authors.lastname: Flatø
authors.forename: Oystein T
authors.initials: OT
authors.lastname: Førre
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.forename: Tore K
authors.initials: TK
authors.lastname: Kvien
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000378:metabolism; D012216:Rheumatic Diseases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013950:Thymus Gland / Q000378:metabolism*
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D020033:Protein Isoforms