title: Comparison of functional variants in IFNL4 and IFNL3 for association with HCV clearance.
abstract: OBJECTIVE
  Genetic polymorphisms within the interferon lambda (IFN-λ) region are strongly associated with hepatitis C virus (HCV) clearance; the IFNL4-ΔG/TT (rs368234815) polymorphism, which controls the generation of IFN-λ4 protein, is more strongly associated with HCV clearance than rs12979860 (the 'IL28B variant'). An IFNL3 3' untranslated region polymorphism (rs4803217) has been proposed as a causal variant that may affect HCV clearance by altering IFNL3 mRNA stability.
  
  
  METHODS
  We compared IFNL4-ΔG/TT and rs4803217 for association with response to pegylated-IFN-α/ribavirin in the VIRAHEP-C and HALT-C trials, and spontaneous HCV clearance in the ALIVE, UHS and WIHS studies. Genotyping was performed with TaqMan assays. We compared differences in mean reduction in HCV RNA levels by genotype and haplotype. For HCV clearance, we calculated p-values comparing c-statistics for IFNL4-ΔG/TT and rs4803217 genotypes by a bootstrap approach.
  
  
  RESULTS
  Among European Americans, linkage disequilibrium between IFNL4-ΔG/TT and rs4803217 was strong (r(2)=0.89-0.99) and there were no significant differences between the variants. In African American (AA) individuals enrolled in VIRAHEP-C, HCV RNA at treatment day 28 was more strongly associated with IFNL4-ΔG/TT than rs4803217 (p=0.003); the IFNL4-ΔG:rs4803217-G haplotype, which includes the putatively favorable IFNL3 allele, was actually associated with the poorest day 28 response (p=0.03, comparison to IFNL4-ΔG:rs4803217-T haplotype). Among AA participants, associations were stronger for IFNL4-ΔG/TT than rs4803217 for undetectable HCV RNA at week 24 in Virahep-C (p=0.03) and week 20 in HALT-C (p=0.03), as well as for spontaneous HCV clearance (p=0.048).
  
  
  CONCLUSIONS
  IFNL4-ΔG/TT is the primary IFN-λ region polymorphism for impaired HCV clearance.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. Electronic address: obrient@mail.nih.gov.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: O'Brien
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pfeiffer
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Paquin
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Krystle A
authors.initials: KA
authors.lastname: Lang Kuhs
authors.affiliation: Information Management Services, Calverton, MD, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Medicine and The Liver-Biliary-Pancreatic Center, Carolinas HealthCare System, Charlotte, NC, USA.
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Bonkovsky
authors.affiliation: National Development and Research Institutes and Weill Cornell Medical College, New York, NY, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Edlin
authors.affiliation: Department of Medicine, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Howell
authors.affiliation: Department of Epidemiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kuniholm
authors.affiliation: VA Long Beach Healthcare System, Long Beach, CA, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Strickler
authors.affiliation: Department of Epidemiology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Thomas
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D000483:Alleles; D000998:Antiviral Agents; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000235:genetics*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D007378:Interleukins; D012367:RNA, Viral; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579163:IFNL4 protein, human
keywords: Genetics; IFNL3; IFNL4; IL28B; Innate immunity; Interferon lambda; Treatment; Viral clearance