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Human Genetics

, Volume 134, Issue 3, pp 279–289 | Cite as

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

  • Etsuko Iio
  • Kentaro Matsuura
  • Nao Nishida
  • Shinya Maekawa
  • Nobuyuki Enomoto
  • Mina Nakagawa
  • Naoya Sakamoto
  • Hiroshi Yatsuhashi
  • Masayuki Kurosaki
  • Namiki Izumi
  • Yoichi Hiasa
  • Naohiko Masaki
  • Tatsuya Ide
  • Keisuke Hino
  • Akihiro Tamori
  • Masao Honda
  • Shuichi Kaneko
  • Satoshi Mochida
  • Hideyuki Nomura
  • Shuhei Nishiguchi
  • Chiaki Okuse
  • Yoshito Itoh
  • Hitoshi Yoshiji
  • Isao Sakaida
  • Kazuhide Yamamoto
  • Hisayoshi Watanabe
  • Shuhei Hige
  • Akihiro Matsumoto
  • Eiji Tanaka
  • Katsushi Tokunaga
  • Yasuhito TanakaEmail author
Original Investigation

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.

Keywords

Sustained Virological Response Rs4794822 Genotype Replication Analysis eQTL Analysis Replication Stage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

439_2014_1520_MOESM1_ESM.pdf (1.1 mb)
Supplementary material 1 (PDF 1171 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Etsuko Iio
    • 1
    • 2
  • Kentaro Matsuura
    • 1
    • 2
  • Nao Nishida
    • 3
    • 4
  • Shinya Maekawa
    • 5
  • Nobuyuki Enomoto
    • 5
  • Mina Nakagawa
    • 6
  • Naoya Sakamoto
    • 6
    • 7
  • Hiroshi Yatsuhashi
    • 8
  • Masayuki Kurosaki
    • 9
  • Namiki Izumi
    • 9
  • Yoichi Hiasa
    • 10
  • Naohiko Masaki
    • 3
  • Tatsuya Ide
    • 11
  • Keisuke Hino
    • 12
  • Akihiro Tamori
    • 13
  • Masao Honda
    • 14
  • Shuichi Kaneko
    • 14
  • Satoshi Mochida
    • 15
  • Hideyuki Nomura
    • 16
  • Shuhei Nishiguchi
    • 17
  • Chiaki Okuse
    • 18
  • Yoshito Itoh
    • 19
  • Hitoshi Yoshiji
    • 20
  • Isao Sakaida
    • 21
  • Kazuhide Yamamoto
    • 22
  • Hisayoshi Watanabe
    • 23
  • Shuhei Hige
    • 7
    • 24
  • Akihiro Matsumoto
    • 25
  • Eiji Tanaka
    • 25
  • Katsushi Tokunaga
    • 4
  • Yasuhito Tanaka
    • 1
    Email author
  1. 1.Department of Virology and Liver UnitNagoya City University Graduate School of Medical SciencesNagoyaJapan
  2. 2.Department of Gastroenterology and MetabolismNagoya City University Graduate School of Medical SciencesNagoyaJapan
  3. 3.The Research Center for Hepatitis and ImmunologyNational Center for Global Health and MedicineIchikawaJapan
  4. 4.Department of Human Genetics, Graduate School of MedicineThe University of TokyoTokyoJapan
  5. 5.First Department of Internal MedicineUniversity of YamanashiChuoJapan
  6. 6.Department of Gastroenterology and HepatologyTokyo Medical and Dental UniversityTokyoJapan
  7. 7.Department of Internal MedicineHokkaido University Graduate School of MedicineSapporoJapan
  8. 8.Clinical Research Center, National Nagasaki Medical CenterOmuraJapan
  9. 9.Division of Gastroenterology and HepatologyMusashino Red Cross HospitalMusashinoJapan
  10. 10.Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonJapan
  11. 11.Division of Gastroenterology, Department of MedicineKurume UniversityKurumeJapan
  12. 12.Department of Hepatology and PancreatologyKawasaki Medical SchoolKurashikiJapan
  13. 13.Department of HepatologyOsaka City Graduate School of MedicineOsakaJapan
  14. 14.Department of GastroenterologyKanazawa University Graduate School of MedicineKanazawaJapan
  15. 15.Division of Gastroenterology and Hepatology, Internal MedicineSaitama Medical UniversityIrumaJapan
  16. 16.The Center for Liver DiseaseShin-Kokura HospitalKitakyushuJapan
  17. 17.Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan
  18. 18.Department of Gastroenterology and HepatologySt. Marianna University School of MedicineKawasakiJapan
  19. 19.Molecular Gastroenterology and HepatologyKyoto Prefectural University of MedicineKyotoJapan
  20. 20.Third Department of Internal MedicineNara Medical UniversityKashiharaJapan
  21. 21.Department of Gastroenterology and HepatologyYamaguchi University Graduate School of MedicineUbeJapan
  22. 22.Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
  23. 23.Department of GastroenterologyYamagata University Faculty of MedicineYamagataJapan
  24. 24.Department of GastroenterologySapporo Kosei General HospitalSapporoJapan
  25. 25.Department of MedicineShinshu University School of MedicineMatsumotoJapan

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