title: Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) induces chronic infection in 50% to 80% of infected persons; approximately 50% of these do not respond to therapy. We performed a genome-wide association study to screen for host genetic determinants of HCV persistence and response to therapy.
  
  
  METHODS
  The analysis included 1362 individuals: 1015 with chronic hepatitis C and 347 who spontaneously cleared the virus (448 were coinfected with human immunodeficiency virus [HIV]). Responses to pegylated interferon alfa and ribavirin were assessed in 465 individuals. Associations between more than 500,000 single nucleotide polymorphisms (SNPs) and outcomes were assessed by multivariate logistic regression.
  
  
  RESULTS
  Chronic hepatitis C was associated with SNPs in the IL28B locus, which encodes the antiviral cytokine interferon lambda. The rs8099917 minor allele was associated with progression to chronic HCV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.74-3.06; P = 6.07 x 10(-9)). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64-3.79; P = 1.96 x 10(-5)) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47-3.18; P = 8.24 x 10(-5)). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90-9.30; P = 3.11 x 10(-8)), with the strongest effects in patients with HCV genotype 1 or 4. This risk allele was identified in 24% of individuals with spontaneous HCV clearance, 32% of chronically infected patients who responded to therapy, and 58% who did not respond (P = 3.2 x 10(-10)). Resequencing of IL28B identified distinct haplotypes that were associated with the clinical phenotype.
  
  
  CONCLUSIONS
  The association of the IL28B locus with natural and treatment-associated control of HCV indicates the importance of innate immunity and interferon lambda in the pathogenesis of HCV infection.
authors.affiliation: University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland. andri.rauch@insel.ch
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.forename: Julia
authors.initials: J
authors.lastname: Di Iulio
authors.forename: Tobias
authors.initials: T
authors.lastname: Mueller
authors.forename: Murielle
authors.initials: M
authors.lastname: Bochud
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.forename: Jan
authors.initials: J
authors.lastname: Borovicka
authors.forename: Sara
authors.initials: S
authors.lastname: Colombo
authors.forename: Andreas
authors.initials: A
authors.lastname: Cerny
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Markus
authors.initials: M
authors.lastname: Heim
authors.forename: Bernard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Raffaele
authors.initials: R
authors.lastname: Malinverni
authors.forename: Darius
authors.initials: D
authors.lastname: Moradpour
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.forename: Andrea
authors.initials: A
authors.lastname: Witteck
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage; D017211:Treatment Failure; D000095022:Interferon Lambda
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C417083:peginterferon alfa-2b