Gastroenterology
Volume 138, Issue 4 , Pages 1338-1345.e7, April 2010

Genetic Variation in IL28B Is Associated With Chronic Hepatitis C and Treatment Failure: A Genome-Wide Association Study

  • Andri Rauch

      Affiliations

    • University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland
    • Corresponding Author InformationAndri Rauch, University Clinic of Infectious Diseases, University Hospital Bern, Inselspital PKT2 B, CH-3010 Bern, Switzerland. fax: (41) 31 328 43 60
    • ,
  • Zoltán Kutalik

      Affiliations

    • Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
    • Swiss Institute of Bioinformatics, Lausanne, Switzerland
    • ,
  • Patrick Descombes

      Affiliations

    • Genomics Platform, National Center of Competence in Research “Frontiers in Genetics,” University of Geneva, Geneva, Switzerland
    • ,
  • Tao Cai

      Affiliations

    • Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Infectious Diseases Service, Department of Internal Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
    • ,
  • Julia Di Iulio

      Affiliations

    • Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • ,
  • Tobias Mueller

      Affiliations

    • Medical Clinic for Hepatology and Gastroenterology, Medical University Charité Campus, Virchow–Klinikum Berlin, Berlin, Germany
    • ,
  • Murielle Bochud

      Affiliations

    • University Institute for Social and Preventive Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
    • ,
  • Manuel Battegay

      Affiliations

    • Infectious Diseases and Infection Control Clinic, Department of Medicine, University Hospital Basel, Basel, Switzerland
    • ,
  • Enos Bernasconi

      Affiliations

    • Infectious Diseases Service, Regional Hospital, Lugano, Switzerland
    • ,
  • Jan Borovicka

      Affiliations

    • Division of Gastroenterology, Canton Hospital St Gallen, St Gallen, Switzerland
    • ,
  • Sara Colombo

      Affiliations

    • Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • ,
  • Andreas Cerny

      Affiliations

    • Liver Unit, Clinica Luganese Moncucco, Lugano, Switzerland
    • ,
  • Jean–François Dufour

      Affiliations

    • Institute of Clinical Pharmacology and Visceral Research, University of Bern, Bern and University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
    • ,
  • Hansjakob Furrer

      Affiliations

    • University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland
    • ,
  • Huldrych F. Günthard

      Affiliations

    • Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
    • ,
  • Markus Heim

      Affiliations

    • Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
    • ,
  • Bernard Hirschel

      Affiliations

    • Division of Infectious Diseases, University Hospital Geneva, Geneva, Switzerland
    • ,
  • Raffaele Malinverni

      Affiliations

    • Pourtalès Hospital, Neuchâtel, Switzerland
    • ,
  • Darius Moradpour

      Affiliations

    • Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland
    • ,
  • Beat Müllhaupt

      Affiliations

    • Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    • ,
  • Andrea Witteck

      Affiliations

    • Infectious Diseases and Infection Control Unit, Canton Hospital St Gallen, St Gallen, Switzerland
    • ,
  • Jacques S. Beckmann

      Affiliations

    • Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
    • Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
    • ,
  • Thomas Berg

      Affiliations

    • Medical Clinic for Hepatology and Gastroenterology, Medical University Charité Campus, Virchow–Klinikum Berlin, Berlin, Germany
    • ,
  • Sven Bergmann

      Affiliations

    • Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
    • Swiss Institute of Bioinformatics, Lausanne, Switzerland
    • ,
  • Francesco Negro

      Affiliations

    • Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland
    • Division of Clinical Pathology, University Hospitals, Geneva, Switzerland
    • ,
  • Amalio Telenti

      Affiliations

    • Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • ,
  • Pierre–Yves Bochud

      Affiliations

    • Institute of Microbiology, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Infectious Diseases Service, Department of Internal Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
    • Corresponding Author InformationReprint requests Address requests for reprints to: Pierre-Yves Bochud, Infectious Diseases Service, Department of Medicine, Institute of Microbiology, Rue du Bugnon 48, CH-1011 Lausanne CHUV, Switzerland. fax: (41) 21 314 40 60
    • ,
  • Swiss Hepatitis C And HIV Cohort Studies

Received 8 October 2009; accepted 29 December 2009. published online 11 January 2010.

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 × 10−9). The association was observed in HCV mono-infected (OR, 2.49; 95% CI, 1.64–3.79; P = 1.96 × 10−5) and HCV/HIV coinfected individuals (OR, 2.16; 95% CI, 1.47–3.18; P = 8.24 × 10−5). rs8099917 was also associated with failure to respond to therapy (OR, 5.19; 95% CI, 2.90–9.30; P = 3.11 × 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 × 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.

Keywords: Hepatitis C, Genetics, Interferon, Interleukin-28

Abbreviations used in this paper: CI, confidence interval, HIV, human immunodeficiency virus, IFN, interferon, OR, odds ratio, SNP, single nucleotide polymorphism

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 Conflicts of interest The authors disclose no conflicts.

 Funding The Swiss Hepatitis C and HIV Cohort Studies are supported by the Swiss National Science Foundation (3347C0-108782/1, grant nos. 3347-069366, 3247-116862, and 3100AO-116323/1, and Swiss HIV Cohort Study grant 543), the Swiss Federal Office for Education and Sciences (03.0599), and the European Commission (LSHM-CT-2004-503359; VIRGIL Network of Excellence on Antiviral Drug Resistance). Genotyping in the Swiss Hepatitis C Cohort Study and statistical analyses were supported by the Leenaards Foundation and Debiopharm S.A. Genotyping in the Swiss HIV Cohort Study was supported by an unrestricted grant by Essex Chemie AG, the Novaris Research Foundation, and Infectigen, Switzerland. P.-Y.B. is supported by the Swiss National Science Foundation (32003B_127613/1), and the Leenaards Foundation.

PII: S0016-5085(10)00008-9

doi:10.1053/j.gastro.2009.12.056

Refers to article:

  • Interleukin-28b: A Key Piece of the Hepatitis C Virus Recovery Puzzle , 24 February 2010

    Chloe L. Thio, David L. Thomas
    Gastroenterology April 2010 (Vol. 138, Issue 4, Pages 1240-1243)

Gastroenterology
Volume 138, Issue 4 , Pages 1338-1345.e7, April 2010

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