Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study

Gastroenterology. 2010 Apr;138(4):1338-45, 1345.e1-7. doi: 10.1053/j.gastro.2009.12.056. Epub 2010 Jan 11.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Genetic Variation
  • Genome-Wide Association Study*
  • Genotype
  • Haplotypes
  • Hepatitis C, Chronic / drug therapy
  • Hepatitis C, Chronic / genetics*
  • Humans
  • Interferon alpha-2
  • Interferon-alpha / administration & dosage
  • Interferons
  • Interleukins / genetics*
  • Male
  • Middle Aged
  • Polyethylene Glycols / administration & dosage
  • Polymorphism, Single Nucleotide*
  • Recombinant Proteins
  • Ribavirin / administration & dosage
  • Treatment Failure

Substances

  • IFNL3 protein, human
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukins
  • Recombinant Proteins
  • Polyethylene Glycols
  • Ribavirin
  • Interferons
  • peginterferon alfa-2b