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

Nature Genetics volume 41, pages 1105–1109 (2009)Cite this article

Abstract

The recommended treatment for patients with chronic hepatitis C, pegylated interferon-α (PEG-IFN-α) 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 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independent cohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 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 × 10−24, and rs8099917, P = 1.11 × 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 × 10−28–2.68 × 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).

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Figure 1: Genome-wide association results with PEG-IFN-α/RBV treatment in 142 Japanese patients with HCV (78 NVR and 64 VR samples).
Figure 2: Genomic structure, P value and OR plots in association analysis and LD map around IL28B and IL28A (chr.19, nucleotide positions 44421319–44461718; build 35).
Figure 3: Quantification of IL28 mRNA expression.

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Acknowledgements

This study was supported by a grant-in-aid from the Ministry of Health, Labour, and Welfare of Japan (H19-kannen-013). This study is based on 15 multicenter hospitals throughout Japan, in the Hokkaido area (Hokkaido University Hospital), Kanto area (Saitama University Hospital; Konodai Hospital; Musashino Red Cross Hospital; Tokyo Medical and Dental University Hospital), Koshin area (Shinshu University Hospital; Kanazawa University Hospital), Tokai area (Nagoya City University Hospital), Kinki area (Kyoto Prefectural University of Medicine Hospital; National Hospital Organization Osaka National Hospital; Hyogo College of Medicine Hospital) and Chugoku/Shikoku area (Tottori University Hospital; Ehime University Hospital; Yamaguchi University Hospital; Kawasaki Medical College Hospital). We thank Y. Uehara-Shibata, Y. Ogasawara, Y. Ishibashi and M. Yamaoka-Sageshima (Tokyo University) for technical assistance; A. Matsumoto (Shinshu), K. Naiki (Saitama), K. Nishimura (Kyoto), H. Enomoto (Hyogo), K. Oyama (Tottori) and the Ochanomizu Liver Conference Study Group for collecting samples; M. Watanabe (Tokyo Medical and Dental University), S. Kaneko (Kanazawa University) and M. Onji (Ehime University) for their advice throughout the study; and H. Ito (Aichi Cancer Center) for conducting statistical analyses.

Author information

Author notes

  1. Yasuhito Tanaka and Nao Nishida: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Yasuhito Tanaka, Masaya Sugiyama, Kentaro Matsuura, Fuminaka Sugauchi & Masashi Mizokami

  2. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Nao Nishida & Katsushi Tokunaga

  3. Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

    Masayuki Kurosaki & Namiki Izumi

  4. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan

    Naoya Sakamoto & Mina Nakagawa

  5. Division of Hepatology and Pancreatology, Kawasaki Medical College, 577 Matsushima, Kurashiki, Japan

    Masaaki Korenaga & Keisuke Hino

  6. Department of Internal Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Shuhei Hige

  7. Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yoshito Ito

  8. National Hospital Organization Osaka National Hospital, Osaka, Japan

    Eiji Mita

  9. Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan

    Eiji Tanaka

  10. Division of Gastroenterology and Hepatology, Internal Medicine, Saitama Medical University, Saitama, Japan

    Satoshi Mochida

  11. Second department of Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan

    Yoshikazu Murawaki

  12. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan

    Masao Honda & Akito Sakai

  13. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan

    Yoichi Hiasa

  14. Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan

    Shuhei Nishiguchi

  15. Central Research Laboratory, Hitachi Ltd., Kokubunji, Japan

    Asako Koike

  16. Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan

    Isao Sakaida

  17. Research Center for Hepatitis and Immunology, International Medical Center of Japan Konodai Hospital, Ichikawa, Japan

    Masatoshi Imamura, Kiyoaki Ito, Koji Yano, Naohiko Masaki & Masashi Mizokami

Authors
  1. Yasuhito Tanaka
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Contributions

Study design and discussion: Y.T., N.N., N.M., K.T., M.M.; sample collection: Y.T., M.K., K.M., N.S., M.N., M.K., K.H., S.H., Y.I., E.M., E.T., S.M., Y.M., M.H., A.S., Y.H., S.N., I.S., M.I., K.I., K.Y., F.S., N.I.; genotyping: N.N.; statistical analysis: N.N., A.K., K.I.; quantitative RT-PCR: M.S.; manuscript writing: Y.T., N.N., K.T., M.M.

Corresponding author

Correspondence to Masashi Mizokami.

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Supplementary Figures 1–3 and Supplementary Tables 1–6 (PDF 726 kb)

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Tanaka, Y., Nishida, N., Sugiyama, M. et al. Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet 41, 1105–1109 (2009). https://doi.org/10.1038/ng.449

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