Combined effects of different interleukin-28B gene variants on the outcome of dual combination therapy in chronic hepatitis C virus type 1 infection

Authors

  • Janett Fischer,

    Corresponding author
    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
    • Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
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    • fax: (0049) 3419712339

  • Stephan Böhm,

    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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  • Markus Scholz,

    1. Institut für Medizinische Informatik, Statistik und Epidemiologie, Universität Leipzig, Leipzig, Germany
    2. LIFE Center (Leipzig Interdisciplinary Research Cluster of Genetic Factors, Phenotypes and Environment), University of Leipzig, Leipzig, Germany
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  • Tobias Müller,

    1. Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
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  • Heiko Witt,

    1. Gastroenterologische Ambulanz der Kinderklinik, Klinikum rechts der Isar TUM, München, Germany
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  • Jacob George,

    1. Storr Liver Unit, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
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  • Christoph Sarrazin,

    1. Department of Internal Medicine I, J. W. Goethe-University Hospital, Frankfurt, Germany
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  • Simone Susser,

    1. Department of Internal Medicine I, J. W. Goethe-University Hospital, Frankfurt, Germany
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  • Eckart Schott,

    1. Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
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  • Vijayaprakash Suppiah,

    1. Storr Liver Unit, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia
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  • David R. Booth,

    1. Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Australia
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  • Graeme J. Stewart,

    1. Institute of Immunology and Allergy Research, Westmead Hospital and Westmead Millennium Institute, University of Sydney, Australia
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  • Florian van Bömmel,

    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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  • Annika Brodzinski,

    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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  • Balazs Fülöp,

    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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  • Pascal Migaud,

    1. Medizinische Klinik m.S. Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany
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  • Thomas Berg

    1. Sektion Hepatologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany
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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the German Competence Network for Viral Hepatitis (Hep-Net), funded by the German Ministry of Education and Research (BMBF, grant no. 01 KI 0437, project no. 10.1.3, and core project no. 10.1 Genetic host factors in viral hepatitis and Genetic Epidemiology Group in viral hepatitis), by the EU-Vigilance Network of Excellence Combating Viral Resistance (VIRGIL, project no. LSHM-CT-2004-503359), and by the BMBF Project: Host and viral determinants for susceptibility and resistance to hepatitis C virus infection (grant no. 01KI0787). Parts of the work were supported by an Australian Research Council Linkage Project Grant (LPO0990067), a National Health and Medical Research Council Grant (1006759), and the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney. M.S. was funded by the Leipzig Interdisciplinary Research Cluster of Genetic Factors, Clinical Phenotypes and Environment (LIFE Center, Universität Leipzig). LIFE is funded by means of the European Union, by the European Regional Development Fund, and by means of the Free State of Saxony within the framework of the excellence initiative.

Abstract

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1–infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700–1710)

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