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HLA-DQA1*05 and upstream variants of PPARGC1B are associated with infliximab persistence in Japanese Crohn’s disease patients

The Pharmacogenomics Journal volume 23, pages 141–148 (2023)Cite this article

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Abstract

Recently, the HLA-DQA1*05 (rs2097432) genetic variation has been reported to be linked to early infliximab (IFX) treatment failure in the Caucasian Crohn’s disease (CD) population, but that evidence is scarce in the Asian population. This study aimed to investigate the relationship between rs2097432 and the cumulative discontinuation-free time of IFX (IFX persistence) in 189 Japanese biologics-naive CD patients. We also performed a genome-wide association study (GWAS) to discover novel genetic predictors for IFX persistence. The C allele of rs2097432 significantly increased the risk of early discontinuation of IFX [Hazard ratio (HR) = 2.23 and P-value = 0.026]. In GWAS, one locus tagged by rs73277969, located upstream of PPARGC1B which attenuates macrophage-mediated inflammation, reached genome-wide significance (HR = 6.04 and P-value = 7.93E−9). Pathway analysis suggested association of signaling by PDGF and FCGR activation signaling with IFX persistence (P-value = 8.56E−5 and 5.80E−4, respectively).

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Fig. 1: Flowchart of this study design.
Fig. 2: Kaplan–Meier curve of discontinuation of infliximab therapy according to the HLA-DQA1*05 (rs2097432) genotype (T/T vs. T/C or CC).
Fig. 3: Manhattan plot of 5,700,568 single-nucleotide polymorphisms utilizing genome-wide association analysis for the relapse-free survival time.
Fig. 4: Results of genome-wide association analysis of discontinuation-free survival rates of Infliximab therapy.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by JSPS KAKENHI Grant Numbers JP15H04805. This work was supported (in part) by the Tohoku Medical Megabank Project (Special Account for reconstruction from the Great East Japan Earthquake). Part of computational resources were provided by the ToMMo supercomputer system. We would like to thank past and present members of the IBD group for fruitful discussions and scientific contributions.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Fumiko Shimoda, Takeo Naito, Yoichi Kakuta, Yusuke Shimoyama, Rintaro Moroi, Hisashi Shiga & Atsushi Masamune

  2. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan

    Yosuke Kawai, Katsushi Tokunaga & Yosuke Omae

  3. Central Biobank, National Center Biobank Network, Shinjuku-ku, Tokyo, Japan

    Katsushi Tokunaga, Eisei Noiri, Koji Kitajima, Yosuke Omae, Reiko Miyahara & Hideyuki Shimanuki

  4. Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Masao Nagasaki

  5. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Masao Nagasaki

  6. Student Health Care Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan

    Yoshitaka Kinouchi

  7. NCVC Biobank, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan

    Hatsue Ishibashi-Ueda, Tsutomu Tomita, Michio Noguchi & Ayako Takahashi

  8. Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    Yu-ichi Goto

  9. Department of Bioresources, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    Sumiko Yoshida, Kotaro Hattori & Ryo Matsumura

  10. Department of Clinical Genome Analysis, Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    Aritoshi Iida

  11. NCGM Biobank, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan

    Yutaka Maruoka & Satoshi Suzuki

  12. AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan

    Hiroyuki Gatanaga

  13. Genome Medical Sciences Project (Konodai), Research Institute, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan

    Masaya Sugiyama

  14. Center for Medical Informatics and Intelligence, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan

    Kengo Miyo

  15. National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Yoichi Matsubara

  16. Center for Regenerative Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Akihiro Umezawa

  17. Department of Maternal-Fetal Biology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Kenichiro Hata

  18. Department of Genome Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Tadashi Kaname

  19. Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan

    Kouichi Ozaki, Haruhiko Tokuda, Hiroshi Watanabe & Shumpei Niida

Authors
  1. Fumiko Shimoda
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  2. Takeo Naito
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  3. Yoichi Kakuta
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  4. Yosuke Kawai
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  6. Yusuke Shimoyama
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  7. Rintaro Moroi
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  8. Hisashi Shiga
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  9. Masao Nagasaki
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  11. Atsushi Masamune
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Consortia

NCBN Controls WGS Consortium

  • Hatsue Ishibashi-Ueda
  • , Tsutomu Tomita
  • , Michio Noguchi
  • , Ayako Takahashi
  • , Yu-ichi Goto
  • , Sumiko Yoshida
  • , Kotaro Hattori
  • , Ryo Matsumura
  • , Aritoshi Iida
  • , Yutaka Maruoka
  • , Hiroyuki Gatanaga
  • , Masaya Sugiyama
  • , Satoshi Suzuki
  • , Kengo Miyo
  • , Yoichi Matsubara
  • , Akihiro Umezawa
  • , Kenichiro Hata
  • , Tadashi Kaname
  • , Kouichi Ozaki
  • , Haruhiko Tokuda
  • , Hiroshi Watanabe
  • , Shumpei Niida
  • , Eisei Noiri
  • , Koji Kitajima
  • , Yosuke Omae
  • , Reiko Miyahara
  • , Hideyuki Shimanuki
  • , Yosuke Kawai
  •  & Katsushi Tokunaga

Contributions

YKakuta, FS, TN, MN and YKinouchi designed the study. FS, TN, YKawai, TK, NCBN Controls WGS Consortium and Y.Kakuta acquired data. FS, TN, YS, RM, HS and YKakuta recruited patients. FS, TN, YKakuta, YKawai and MN analyzed data. FS, TN, YKakuta, YKawai and AM drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Takeo Naito.

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Competing interests

YKakuta received research grants from AbbVie Inc., Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., JIMRO Co., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co. Ltd., Daiichi Sankyo Co. Ltd, Kyowa Kirin Co. Ltd., and Janssen Pharmaceutical K.K. MN received research grants from Toshiba Corporation. AM received research grants from Takeda Pharmaceutical Co. Ltd., AbbVie Inc., Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., JIMRO Co. Ltd., Mochida Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.

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Shimoda, F., Naito, T., Kakuta, Y. et al. HLA-DQA1*05 and upstream variants of PPARGC1B are associated with infliximab persistence in Japanese Crohn’s disease patients. Pharmacogenomics J 23, 141–148 (2023). https://doi.org/10.1038/s41397-023-00312-z

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