IFNL4 and IFNL3 associated polymorphisms strongly influence the spontaneous IFN-alpha receptor-1 expression in HCV-infected patients

PLoS One. 2015 Feb 12;10(2):e0117397. doi: 10.1371/journal.pone.0117397. eCollection 2015.

Abstract

Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Female
  • Gene Expression Regulation*
  • Genotype
  • Hepacivirus* / genetics
  • Hepatitis C / genetics*
  • Hepatitis C / virology
  • Hepatitis C, Chronic / genetics
  • Humans
  • Interferon-alpha / pharmacology
  • Interferons
  • Interleukins / genetics*
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • RNA, Messenger / genetics
  • Receptor, Interferon alpha-beta / genetics*
  • Viral Load

Substances

  • IFNAR1 protein, human
  • IFNL3 protein, human
  • IFNL4 protein, human
  • Interferon-alpha
  • Interleukins
  • RNA, Messenger
  • Receptor, Interferon alpha-beta
  • Interferons

Grant support

This work was partly supported by grants from Italian Ministry of Health, Ricerca Corrente and Ricerca Finalizzata. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.