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Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

Author

Listed:
  • Saori Sakaue

    (Osaka University Graduate School of Medicine
    Graduate School of Medicine, the University of Tokyo
    Harvard Medical School
    Brigham and Women’s Hospital, Harvard Medical School)

  • Etsuro Yamaguchi

    (School of Medicine, Aichi Medical University)

  • Yoshikazu Inoue

    (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai)

  • Meiko Takahashi

    (Kyoto University Graduate School of Medicine)

  • Jun Hirata

    (Osaka University Graduate School of Medicine
    Pharmaceutical Discovery Research Laboratories, TEIJIN PHARMA LIMITED)

  • Ken Suzuki

    (Osaka University Graduate School of Medicine)

  • Satoru Ito

    (School of Medicine, Aichi Medical University)

  • Toru Arai

    (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai)

  • Masaki Hirose

    (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai)

  • Yoshinori Tanino

    (Fukushima Medical University)

  • Takefumi Nikaido

    (Fukushima Medical University)

  • Toshio Ichiwata

    (Tokyo Medical University)

  • Shinya Ohkouchi

    (Tohoku University)

  • Taizou Hirano

    (Tohoku University)

  • Toshinori Takada

    (Niigata University Medical and Dental Hospital)

  • Satoru Miyawaki

    (Faculty of Medicine, the University of Tokyo)

  • Shogo Dofuku

    (Faculty of Medicine, the University of Tokyo)

  • Yuichi Maeda

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Takuro Nii

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Toshihiro Kishikawa

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Kotaro Ogawa

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Tatsuo Masuda

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Kenichi Yamamoto

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Kyuto Sonehara

    (Osaka University Graduate School of Medicine)

  • Ryushi Tazawa

    (Tokyo Medical and Dental University)

  • Konosuke Morimoto

    (Institute of Tropical Medicine, Nagasaki University)

  • Masahiro Takaki

    (Nagasaki University Hospital, Nagasaki University)

  • Satoshi Konno

    (Faculty of Medicine and Graduate School of Medicine, Hokkaido University)

  • Masaru Suzuki

    (Faculty of Medicine and Graduate School of Medicine, Hokkaido University)

  • Keisuke Tomii

    (Kobe City Medical Center General Hospital)

  • Atsushi Nakagawa

    (Kobe City Medical Center General Hospital)

  • Tomohiro Handa

    (Graduate School of Medicine, Kyoto University)

  • Kiminobu Tanizawa

    (Graduate School of Medicine, Kyoto University)

  • Haruyuki Ishii

    (Kyorin University)

  • Manabu Ishida

    (Kyorin University)

  • Toshiyuki Kato

    (Kariya Toyota General Hospital)

  • Naoya Takeda

    (Kariya Toyota General Hospital)

  • Koshi Yokomura

    (Respiratory Disease Center, Seirei Mikatahara General Hospital)

  • Takashi Matsui

    (Respiratory Disease Center, Seirei Mikatahara General Hospital)

  • Masaki Watanabe

    (Graduate School of Medical & Dental Sciences, Kagoshima University)

  • Hiromasa Inoue

    (Graduate School of Medical & Dental Sciences, Kagoshima University)

  • Kazuyoshi Imaizumi

    (Fujita Health University School of Medicine)

  • Yasuhiro Goto

    (Fujita Health University School of Medicine)

  • Hiroshi Kida

    (Osaka University Graduate School of Medicine
    National Hospital Organization Osaka Toneyama Medical Center)

  • Tomoyuki Fujisawa

    (Hamamatsu University School of Medicine)

  • Takafumi Suda

    (Hamamatsu University School of Medicine)

  • Takashi Yamada

    (Shizuoka City Shizuoka Hospital)

  • Yasuomi Satake

    (Shizuoka City Shizuoka Hospital)

  • Hidenori Ibata

    (National Hospital Organization Mie Chuo Medical Center)

  • Nobuyuki Hizawa

    (Faculty of Medicine, University of Tsukuba)

  • Hideki Mochizuki

    (Osaka University Graduate School of Medicine)

  • Atsushi Kumanogoh

    (Osaka University Graduate School of Medicine
    World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University
    Institute for Open and Transdisciplinary Research Initiatives, Osaka University)

  • Fumihiko Matsuda

    (Kyoto University Graduate School of Medicine)

  • Koh Nakata

    (Niigata University Medical and Dental Hospital)

  • Tomomitsu Hirota

    (the Jikei University School of Medicine, Research Center for Medical Science)

  • Mayumi Tamari

    (the Jikei University School of Medicine, Research Center for Medical Science)

  • Yukinori Okada

    (Osaka University Graduate School of Medicine
    Institute for Open and Transdisciplinary Research Initiatives, Osaka University
    World Premier International Immunology Frontier Research Center (WPI-IFReC), Osaka University)

Abstract

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10−12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10−12), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10−7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.

Suggested Citation

  • Saori Sakaue & Etsuro Yamaguchi & Yoshikazu Inoue & Meiko Takahashi & Jun Hirata & Ken Suzuki & Satoru Ito & Toru Arai & Masaki Hirose & Yoshinori Tanino & Takefumi Nikaido & Toshio Ichiwata & Shinya , 2021. "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21011-y
    DOI: 10.1038/s41467-021-21011-y
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    Cited by:

    1. Kenichi Yamamoto & Kyuto Sonehara & Shinichi Namba & Takahiro Konuma & Hironori Masuko & Satoru Miyawaki & Yoichiro Kamatani & Nobuyuki Hizawa & Keiichi Ozono & Loic Yengo & Yukinori Okada, 2023. "Genetic footprints of assortative mating in the Japanese population," Nature Human Behaviour, Nature, vol. 7(1), pages 65-73, January.
    2. Kyuto Sonehara & Yui Kimura & Yoshiko Nakano & Tatsuya Ozawa & Meiko Takahashi & Ken Suzuki & Takashi Fujii & Yuko Matsushita & Arata Tomiyama & Toshihiro Kishikawa & Kenichi Yamamoto & Tatsuhiko Nait, 2022. "A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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