Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C

Nat Genet. 2009 Oct;41(10):1105-9. doi: 10.1038/ng.449. Epub 2009 Sep 13.

Abstract

The recommended treatment for patients with chronic hepatitis C, pegylated interferon-alpha (PEG-IFN-alpha) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 x 10(-13), and rs8099917, 3.11 x 10(-15)). We replicated these associations in an independent cohort (combined P values, 2.84 x 10(-27) (OR = 17.7; 95% CI = 10.0-31.3) and 2.68 x 10(-32) (OR = 27.1; 95% CI = 14.6-50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 x 10(-24), and rs8099917, P = 1.11 x 10(-27)). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 x 10(-28)-2.68 x 10(-32); OR = 22.3-27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antiviral Agents / therapeutic use*
  • Asian Continental Ancestry Group / genetics
  • Chromosomes, Human, Pair 19
  • Drug Combinations
  • Female
  • Genome, Human
  • Genome-Wide Association Study*
  • Haplotypes
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / virology
  • Humans
  • Interferon-alpha / therapeutic use*
  • Interferons
  • Interleukins / genetics*
  • Male
  • Polymorphism, Single Nucleotide*
  • Ribavirin / therapeutic use*
  • Treatment Outcome

Substances

  • Antiviral Agents
  • Drug Combinations
  • IFNL3 protein, human
  • Interferon-alpha
  • Interleukins
  • Ribavirin
  • Interferons