title: The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome.
abstract: 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.
  
  
  METHODS
  The exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms.
  
  
  RESULTS
  Carriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5-2.7], P = 6.6 x 10(-6)). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN-induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026).
  
  
  CONCLUSIONS
  Our findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN-induced genes in PBMCs.
authors: INSERM U 802, Université Paris-Sud 11, Le Kremlin Bicêtre, France.
authors: Corinne
authors: C
authors: Miceli-Richard
authors: Nicolas
authors: N
authors: Gestermann
authors: Marc
authors: M
authors: Ittah
authors: Emmanuelle
authors: E
authors: Comets
authors: Pascale
authors: P
authors: Loiseau
authors: Xavier
authors: X
authors: Puechal
authors: Eric
authors: E
authors: Hachulla
authors: Jacques-Eric
authors: JE
authors: Gottenberg
authors: Pierre
authors: P
authors: Lebon
authors: Laurent
authors: L
authors: Becquemont
authors: Xavier
authors: X
authors: Mariette
mesh_terms: D000483:Alleles; D001706:Biopsy; D016022:Case-Control Studies; D015331:Cohort Studies; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D016254:Mutagenesis, Insertional / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D012469:Salivary Glands / Q000378:metabolism / Q000473:pathology; D012859:Sjogren's Syndrome / Q000235:genetics*
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D012333:RNA, Messenger