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

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.

• Authors: Andri Rauch, Zoltán Kutalik, Patrick Descombes, Tao Cai, Julia Di Iulio, Tobias Mueller, Murielle Bochud, Manuel Battegay, Enos Bernasconi, Jan Borovicka, Sara Colombo, Andreas Cerny, Jean-François Dufour, Hansjakob Furrer, Huldrych F Günthard, Markus Heim, Bernard Hirschel, Raffaele Malinverni, Darius Moradpour, Beat Müllhaupt, Andrea Witteck, Jacques S Beckmann, Thomas Berg, Sven Bergmann, Francesco Negro, Amalio Telenti, Pierre-Yves Bochud, Swiss Hepatitis C Cohort Study, Swiss HIV Cohort Study
• Journal: Gastroenterology (Gastroenterology) Vol. 138 Issue 4 Pg. 1338-45, 1345.e1-7 (Apr 2010) ISSN: 1528-0012 [Electronic] United States
• PMID: 20060832 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

• Adult
• Aged
• Female
• Genetic Variation
• Genome-Wide Association Study
• Genotype
• Haplotypes
• Hepatitis C, Chronic (drug therapy, 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