title: Interferon gamma receptor 2 gene variants are associated with liver fibrosis in patients with chronic hepatitis C infection.
abstract: BACKGROUND
  Only a minority of patients with chronic hepatitis C virus (HCV) infection develops severe liver fibrosis, a process that may be controlled by human genetic factors.
  
  
  OBJECTIVE
  To investigate the role of 384 single nucleotide polymorphisms (SNPs) located in 36 candidate genes related to the fibrogenesis/fibrolysis process.
  
  
  METHODS
  Patients with chronic HCV infection were gathered from two French cohorts (prospectively and retrospectively). The overall sample consisted of 393 HCV-infected subjects without known risk factors for fibrosis progression, including 134 patients with severe liver fibrosis and 259 without severe fibrosis.
  
  
  RESULTS
  Only two SNPs in strong linkage disequilibrium (LD) in the interferon gamma receptor 2 gene (IFNGR2) were significantly associated with liver fibrosis in both the prospective and the retrospective samples. The strongest association (p=8x10(-5)) was observed with the G/A SNP rs9976971 with an OR of severe fibrosis for AA versus AG or GG subjects at 2.95 (95% CI 1.70 to 5.11). This effect was higher (p=9x10(-7)) when taking into account the time of follow-up, and the hazard ratio of progression towards severe fibrosis for AA patients was 2.62 (1.76 to 3.91). Refined sequencing and analysis of the IFNGR2 region identified two additional variants in strong LD with rs9976971. No haplotypes derived from this cluster of four variants provided stronger evidence for association than rs9976971 alone.
  
  
  CONCLUSIONS
  This identification of a cluster of four IFNGR2 variants strongly associated with fibrosis progression in chronic HCV infection underlines the role of IFNgamma in the development of liver fibrosis that may pave the way for new treatments.
authors.affiliation: Unité d'Hépatologie, Institut National de la Santé et de la Recherche Médicale, U567, Hôpital Cochin, Paris, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nalpas
authors.forename: Roubila
authors.initials: R
authors.lastname: Lavialle-Meziani
authors.forename: Sabine
authors.initials: S
authors.lastname: Plancoulaine
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Antoine
authors.initials: A
authors.lastname: Nalpas
authors.forename: Mona
authors.initials: M
authors.lastname: Munteanu
authors.forename: Frederic
authors.initials: F
authors.lastname: Charlotte
authors.forename: Brigitte
authors.initials: B
authors.lastname: Ranque
authors.forename: Etienne
authors.initials: E
authors.lastname: Patin
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Hélène
authors.initials: H
authors.lastname: Fontaine
authors.forename: Anaïs
authors.initials: A
authors.lastname: Vallet-Pichard
authors.forename: Dominique
authors.initials: D
authors.lastname: Pontoire
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D015810:Linkage Disequilibrium; D008103:Liver Cirrhosis / Q000235:genetics* / Q000821:virology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017471:Receptors, Interferon / Q000235:genetics*; D055815:Young Adult
chemical_list: C086185:IFNGR2 protein, human; D017471:Receptors, Interferon