Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

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 Ohkouchi, Taizou Hirano, Toshinori Takada, Satoru Miyawaki, Shogo Dofuku, Yuichi Maeda, Takuro Nii, Toshihiro Kishikawa, Kotaro Ogawa, Tatsuo Masuda, Kenichi Yamamoto, Kyuto Sonehara, Ryushi Tazawa, Konosuke Morimoto, Masahiro Takaki, Satoshi Konno, Masaru Suzuki, Keisuke Tomii, Atsushi Nakagawa, Tomohiro Handa, Kiminobu Tanizawa, Haruyuki Ishii, Manabu Ishida, Toshiyuki Kato, Naoya Takeda, Koshi Yokomura, Takashi Matsui, Masaki Watanabe, Hiromasa Inoue, Kazuyoshi Imaizumi, Yasuhiro Goto, Hiroshi Kida, Tomoyuki Fujisawa, Takafumi Suda, Takashi Yamada, Yasuomi Satake, Hidenori Ibata, Nobuyuki Hizawa, Hideki Mochizuki, Atsushi Kumanogoh, Fumihiko Matsuda, Koh Nakata, Tomomitsu Hirota, Mayumi Tamari and Yukinori Okada ()
Additional contact information
Saori Sakaue: Osaka University Graduate School of Medicine
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
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
Takuro Nii: Osaka University Graduate School of Medicine
Toshihiro Kishikawa: Osaka University Graduate School of Medicine
Kotaro Ogawa: Osaka University Graduate School of Medicine
Tatsuo Masuda: Osaka University Graduate School of Medicine
Kenichi Yamamoto: 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
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-6

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21011-y

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