title: Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.
abstract: The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected.
  
  
  CONCLUSIONS
  We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.
authors.affiliation: Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Julia
authors.initials: J
authors.lastname: di Iulio
authors.forename: Angela
authors.initials: A
authors.lastname: Ciuffi
authors.forename: Karen
authors.initials: K
authors.lastname: Fitzmaurice
authors.forename: Dermot
authors.initials: D
authors.lastname: Kelleher
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Raquel
authors.initials: R
authors.lastname: Martinez
authors.forename: Sara
authors.initials: S
authors.lastname: Pulit
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.forename: Patrick
authors.initials: P
authors.lastname: Schmid
authors.forename: Bernard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
mesh_terms: D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000821:virology*; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000502:physiology; D012075:Remission, Spontaneous; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda