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Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C

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Abstract

Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10−7 in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.

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Acknowledgments

We thank Ms. Yasuka Uehara-Shibata, Yuko Ogasawara-Hirano, Yoshimi Ishibashi, Natsumi Baba, Megumi Yamaoka-Sageshima, Takayo Tsuchiura, Yoriko Mawatari (Tokyo University), and Dr. Shintaro Ogawa (Nagoya City University) for technical assistance. This work was supported by the Ministry of Health, Labor, and Welfare of Japan (H25-kanen-ippan-005) to Yasuhito Tanka and Katsushi Tokunaga, KAKENHI (22133008) Grant-in-Aid for Scientific Research on Innovative Areas to Katsushi Tokunaga, and KAKENHI (24790728) Grant-in-Aid from the Ministry of Education, Culture, Sports, Science of Japan for Young Scientists (B) to Nao Nishida.

Conflict of interest

The following authors are currently conducting research sponsored by the companies: Yasuhito Tanaka, Keisuke Hino, and Yoshito Itoh by Merck Sharp & Dohme, Corp., Chugai Pharmaceutical Co., Ltd., and Bristol-Myers Squibb; Nobuyuki Enomoto, Shuhei Nishiguchi, and Eiji Tanaka by Merck Sharp & Dohme, Corp. and Chugai Pharmaceutical Co., Ltd.; Naoya Sakamoto by Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Merck Sharp & Dohme, Corp., and Otsuka Pharmaceutical Co., Ltd.; Hiroshi Yatsuhashi by Chugai Pharmaceutical Co., Ltd.; Akihiro Tamori by Merck Sharp & Dohme, Corp.; Satoshi Mochida by Merck Sharp & Dohme, Corp., Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, and Toray Medical Co., Ltd. The other authors have no conflict of interest.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Authors and Affiliations

  1. Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, 467-8601, Japan

    Etsuko Iio, Kentaro Matsuura & Yasuhito Tanaka

  2. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan

    Etsuko Iio & Kentaro Matsuura

  3. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan

    Nao Nishida & Naohiko Masaki

  4. Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan

    Nao Nishida & Katsushi Tokunaga

  5. First Department of Internal Medicine, University of Yamanashi, Chuo, 409-3898, Japan

    Shinya Maekawa & Nobuyuki Enomoto

  6. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, 113-0034, Japan

    Mina Nakagawa & Naoya Sakamoto

  7. Department of Internal Medicine, Hokkaido University Graduate School of Medicine, Sapporo, 060-0814, Japan

    Naoya Sakamoto & Shuhei Hige

  8. Clinical Research Center, National Nagasaki Medical Center, Omura, 856-8562, Japan

    Hiroshi Yatsuhashi

  9. Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, 180-0023, Japan

    Masayuki Kurosaki & Namiki Izumi

  10. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, 791-0295, Japan

    Yoichi Hiasa

  11. Division of Gastroenterology, Department of Medicine, Kurume University, Kurume, 830-0011, Japan

    Tatsuya Ide

  12. Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, 701-0114, Japan

    Keisuke Hino

  13. Department of Hepatology, Osaka City Graduate School of Medicine, Osaka, 545-8585, Japan

    Akihiro Tamori

  14. Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-0934, Japan

    Masao Honda & Shuichi Kaneko

  15. Division of Gastroenterology and Hepatology, Internal Medicine, Saitama Medical University, Iruma, 350-0495, Japan

    Satoshi Mochida

  16. The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, 803-8505, Japan

    Hideyuki Nomura

  17. Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, 663-8131, Japan

    Shuhei Nishiguchi

  18. Department of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, 216-8511, Japan

    Chiaki Okuse

  19. Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, 602-0841, Japan

    Yoshito Itoh

  20. Third Department of Internal Medicine, Nara Medical University, Kashihara, 634-8522, Japan

    Hitoshi Yoshiji

  21. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, 755-8505, Japan

    Isao Sakaida

  22. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, 700-0914, Japan

    Kazuhide Yamamoto

  23. Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, 990-9585, Japan

    Hisayoshi Watanabe

  24. Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, 060-0033, Japan

    Shuhei Hige

  25. Department of Medicine, Shinshu University School of Medicine, Matsumoto, 390-8621, Japan

    Akihiro Matsumoto & Eiji Tanaka

Authors
  1. Etsuko Iio
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  2. Kentaro Matsuura
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  3. Nao Nishida
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  4. Shinya Maekawa
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  5. Nobuyuki Enomoto
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  8. Hiroshi Yatsuhashi
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  9. Masayuki Kurosaki
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  10. Namiki Izumi
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  11. Yoichi Hiasa
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  12. Naohiko Masaki
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  13. Tatsuya Ide
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  14. Keisuke Hino
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  15. Akihiro Tamori
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  16. Masao Honda
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  17. Shuichi Kaneko
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  18. Satoshi Mochida
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  19. Hideyuki Nomura
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  20. Shuhei Nishiguchi
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  21. Chiaki Okuse
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  22. Yoshito Itoh
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  23. Hitoshi Yoshiji
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  24. Isao Sakaida
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  25. Kazuhide Yamamoto
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  26. Hisayoshi Watanabe
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  27. Shuhei Hige
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  28. Akihiro Matsumoto
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  29. Eiji Tanaka
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  30. Katsushi Tokunaga
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  31. Yasuhito Tanaka
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Corresponding author

Correspondence to Yasuhito Tanaka.

Additional information

E. Iio and K. Matsuura equally contributed to this work (shared first authorship).

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Iio, E., Matsuura, K., Nishida, N. et al. Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. Hum Genet 134, 279–289 (2015). https://doi.org/10.1007/s00439-014-1520-7

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  • DOI: https://doi.org/10.1007/s00439-014-1520-7

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