title: Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus.
abstract: OBJECTIVE
  Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.
  
  
  METHODS
  IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype.
  
  
  RESULTS
  IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression.
  
  
  CONCLUSIONS
  This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
authors.affiliation: University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Feng
authors.forename: Rivka C
authors.initials: RC
authors.lastname: Stone
authors.forename: Maija-Leena
authors.initials: ML
authors.lastname: Eloranta
authors.forename: Niquiche
authors.initials: N
authors.lastname: Sangster-Guity
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Chuan
authors.initials: C
authors.lastname: Wang
authors.forename: Gunnar
authors.initials: G
authors.lastname: Alm
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Barnes
mesh_terms: D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D016898:Interferon-alpha / Q000097:blood; D007962:Leukocytes / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha