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; Yukinori Okada

doi:10.1038/s41467-021-21011-y

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 KishikawaKotaro 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, Yukinori Okada

Respiratory Medicine & Clinical Allergy

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

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.

Original language	English
Article number	1032
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21011-y
Publication status	Published - 01-12-2021

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-021-21011-y

Cite this

Sakaue, S., Yamaguchi, E., Inoue, Y., Takahashi, M., Hirata, J., Suzuki, K., Ito, S., Arai, T., Hirose, M., Tanino, Y., Nikaido, T., Ichiwata, T., Ohkouchi, S., Hirano, T., Takada, T., Miyawaki, S., Dofuku, S., Maeda, Y., Nii, T., ... Okada, Y. (2021). Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis. Nature communications, 12(1), Article 1032. https://doi.org/10.1038/s41467-021-21011-y

@article{cc3e112bb3574f65bfce1271959b745e,

title = "Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis",

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.",

author = "Saori Sakaue and Etsuro Yamaguchi and Yoshikazu Inoue and Meiko Takahashi and Jun Hirata and Ken Suzuki and Satoru Ito and Toru Arai and Masaki Hirose and Yoshinori Tanino and Takefumi Nikaido and Toshio Ichiwata and Shinya Ohkouchi and Taizou Hirano and Toshinori Takada and Satoru Miyawaki and Shogo Dofuku and Yuichi Maeda and Takuro Nii and Toshihiro Kishikawa and Kotaro Ogawa and Tatsuo Masuda and Kenichi Yamamoto and Kyuto Sonehara and Ryushi Tazawa and Konosuke Morimoto and Masahiro Takaki and Satoshi Konno and Masaru Suzuki and Keisuke Tomii and Atsushi Nakagawa and Tomohiro Handa and Kiminobu Tanizawa and Haruyuki Ishii and Manabu Ishida and Toshiyuki Kato and Naoya Takeda and Koshi Yokomura and Takashi Matsui and Masaki Watanabe and Hiromasa Inoue and Kazuyoshi Imaizumi and Yasuhiro Goto and Hiroshi Kida and Tomoyuki Fujisawa and Takafumi Suda and Takashi Yamada and Yasuomi Satake and Hidenori Ibata and Nobuyuki Hizawa and Hideki Mochizuki and Atsushi Kumanogoh and Fumihiko Matsuda and Koh Nakata and Tomomitsu Hirota and Mayumi Tamari and Yukinori Okada",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-21011-y",

language = "English",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Sakaue, S, Yamaguchi, E, Inoue, Y, Takahashi, M, Hirata, J, Suzuki, K, Ito, S, Arai, T, Hirose, M, Tanino, Y, Nikaido, T, Ichiwata, T, Ohkouchi, S, Hirano, T, Takada, T, Miyawaki, S, Dofuku, S, Maeda, Y, Nii, T, Kishikawa, T, Ogawa, K, Masuda, T, Yamamoto, K, Sonehara, K, Tazawa, R, Morimoto, K, Takaki, M, Konno, S, Suzuki, M, Tomii, K, Nakagawa, A, Handa, T, Tanizawa, K, Ishii, H, Ishida, M, Kato, T, Takeda, N, Yokomura, K, Matsui, T, Watanabe, M, Inoue, H, Imaizumi, K , Goto, Y, Kida, H, Fujisawa, T, Suda, T, Yamada, T, Satake, Y, Ibata, H, Hizawa, N, Mochizuki, H, Kumanogoh, A, Matsuda, F, Nakata, K, Hirota, T, Tamari, M & Okada, Y 2021, 'Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis', Nature communications, vol. 12, no. 1, 1032. https://doi.org/10.1038/s41467-021-21011-y

TY - JOUR

T1 - Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

AU - Sakaue, Saori

AU - Yamaguchi, Etsuro

AU - Inoue, Yoshikazu

AU - Takahashi, Meiko

AU - Hirata, Jun

AU - Suzuki, Ken

AU - Ito, Satoru

AU - Arai, Toru

AU - Hirose, Masaki

AU - Tanino, Yoshinori

AU - Nikaido, Takefumi

AU - Ichiwata, Toshio

AU - Ohkouchi, Shinya

AU - Hirano, Taizou

AU - Takada, Toshinori

AU - Miyawaki, Satoru

AU - Dofuku, Shogo

AU - Maeda, Yuichi

AU - Nii, Takuro

AU - Kishikawa, Toshihiro

AU - Ogawa, Kotaro

AU - Masuda, Tatsuo

AU - Yamamoto, Kenichi

AU - Sonehara, Kyuto

AU - Tazawa, Ryushi

AU - Morimoto, Konosuke

AU - Takaki, Masahiro

AU - Konno, Satoshi

AU - Suzuki, Masaru

AU - Tomii, Keisuke

AU - Nakagawa, Atsushi

AU - Handa, Tomohiro

AU - Tanizawa, Kiminobu

AU - Ishii, Haruyuki

AU - Ishida, Manabu

AU - Kato, Toshiyuki

AU - Takeda, Naoya

AU - Yokomura, Koshi

AU - Matsui, Takashi

AU - Watanabe, Masaki

AU - Inoue, Hiromasa

AU - Imaizumi, Kazuyoshi

AU - Goto, Yasuhiro

AU - Kida, Hiroshi

AU - Fujisawa, Tomoyuki

AU - Suda, Takafumi

AU - Yamada, Takashi

AU - Satake, Yasuomi

AU - Ibata, Hidenori

AU - Hizawa, Nobuyuki

AU - Mochizuki, Hideki

AU - Kumanogoh, Atsushi

AU - Matsuda, Fumihiko

AU - Nakata, Koh

AU - Hirota, Tomomitsu

AU - Tamari, Mayumi

AU - Okada, Yukinori

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85101445852&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85101445852&partnerID=8YFLogxK

U2 - 10.1038/s41467-021-21011-y

DO - 10.1038/s41467-021-21011-y

M3 - Article

C2 - 33589587

AN - SCOPUS:85101445852

SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1032

ER -

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this