title: IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes.
abstract: Genetic polymorphisms near IL28B are associated with spontaneous and treatment-induced clearance of hepatitis C virus (HCV), two processes that require the appropriate activation of the host immune responses. Intrahepatic inflammation is believed to mirror such activation, but its relationship with IL28B polymorphisms has yet to be fully appreciated. We analyzed the association of IL28B polymorphisms with histological and follow-up features in 2335 chronically HCV-infected Caucasian patients. Assessable phenotypes before any antiviral treatment included necroinflammatory activity (n = 1,098), fibrosis (n = 1,527), fibrosis progression rate (n = 1,312), and hepatocellular carcinoma development (n = 1,915). Associations of alleles with the phenotypes were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. The rare G allele at IL28B marker rs8099917-previously shown to be at risk of treatment failure-was associated with lower activity (P = 0.04), lower fibrosis (P = 0.02) with a trend toward lower fibrosis progression rate (P = 0.06). When stratified according to HCV genotype, most significant associations were observed in patients infected with non-1 genotypes (P = 0.003 for activity, P = 0.001 for fibrosis, and P = 0.02 for fibrosis progression rate), where the odds ratio of having necroinflammation or rapid fibrosis progression for patients with IL28B genotypes TG or GG versus TT were 0.48 (95% confidence intervals 0.30-0.78) and 0.56 (0.35-0.92), respectively. IL28B polymorphisms were not predictive of the development of hepatocellular carcinoma.
  
  
  CONCLUSIONS
  In chronic hepatitis C, IL28B variants associated with poor response to interferon therapy may predict slower fibrosis progression, especially in patients infected with non-1 HCV genotypes.
authors.affiliation: Service of Infectious Diseases, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bibert
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Etienne
authors.initials: E
authors.lastname: Patin
authors.forename: Julien
authors.initials: J
authors.lastname: Guergnon
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nalpas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goossens
authors.forename: Lorenz
authors.initials: L
authors.lastname: Kuske
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Tillman
authors.initials: T
authors.lastname: Gerlach
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.forename: Stephan
authors.initials: S
authors.lastname: Regenass
authors.forename: Guenter
authors.initials: G
authors.lastname: Dollenmaier
authors.forename: Hans
authors.initials: H
authors.lastname: Hirsch
authors.forename: Gladys
authors.initials: G
authors.lastname: Martinetti
authors.forename: Meri
authors.initials: M
authors.lastname: Gorgiewski
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.forename: Ioannis
authors.initials: I
authors.lastname: Theodorou
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
mesh_terms: D000328:Adult; D000483:Alleles; D018450:Disease Progression; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000821:virology; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda