IgG4-related disease in the Japanese population: a genome-wide association study

Chikashi Terao; Masao Ota; Takeshi Iwasaki; Masahiro Shiokawa; Shuji Kawaguchi; Katsutoshi Kuriyama; Takahisa Kawaguchi; Yuzo Kodama; Izumi Yamaguchi; Kazushige Uchida; Koichiro Higasa; Motohisa Yamamoto; Kensuke Kubota; Shujiro Yazumi; Kenji Hirano; Yasufumi Masaki; Hiroyuki Maguchi; Tomoki Origuchi; Shoko Matsui; Takahiro Nakazawa; Hideyuki Shiomi; Terumi Kamisawa; Osamu Hasebe; Eisuke Iwasaki; Kazuo Inui; Yoshiya Tanaka; Koh-Ichi Ohshima; Takashi Akamizu; Shigeo Nakamura; Seiji Nakamura; Takako Saeki; Hisanori Umehara; Tooru Shimosegawa; Nobumasa Mizuno; Mitsuhiro Kawano; Atsushi Azumi; Hiroki Takahashi; Tsuneyo Mimori; Yoichiro Kamatani; Kazuichi Okazaki; Tsutomu Chiba; Shigeyuki Kawa; Fumihiko Matsuda; Japanese IgG4-Related Disease Working Consortium

doi:10.1016/S2665-9913(19)30006-2

IgG4-related disease in the Japanese population: a genome-wide association study

Lancet Rheumatol. 2019 Sep;1(1):e14-e22. doi: 10.1016/S2665-9913(19)30006-2. Epub 2019 Aug 6.

Authors

Chikashi Terao¹, Masao Ota², Takeshi Iwasaki³, Masahiro Shiokawa⁴, Shuji Kawaguchi¹, Katsutoshi Kuriyama⁴, Takahisa Kawaguchi¹, Yuzo Kodama⁴, Izumi Yamaguchi¹, Kazushige Uchida⁵, Koichiro Higasa¹, Motohisa Yamamoto⁶, Kensuke Kubota⁷, Shujiro Yazumi⁸, Kenji Hirano⁹, Yasufumi Masaki¹⁰, Hiroyuki Maguchi¹¹, Tomoki Origuchi¹², Shoko Matsui¹³, Takahiro Nakazawa¹⁴, Hideyuki Shiomi¹⁵, Terumi Kamisawa¹⁶, Osamu Hasebe¹⁷, Eisuke Iwasaki¹⁸, Kazuo Inui¹⁹, Yoshiya Tanaka²⁰, Koh-Ichi Ohshima²¹, Takashi Akamizu²², Shigeo Nakamura²³, Seiji Nakamura²⁴, Takako Saeki²⁵, Hisanori Umehara²⁶, Tooru Shimosegawa²⁷, Nobumasa Mizuno²⁸, Mitsuhiro Kawano²⁹, Atsushi Azumi³⁰, Hiroki Takahashi⁶, Tsuneyo Mimori³¹, Yoichiro Kamatani¹, Kazuichi Okazaki⁵, Tsutomu Chiba⁴, Shigeyuki Kawa³², Fumihiko Matsuda³³; Japanese IgG4-Related Disease Working Consortium

Collaborators

Japanese IgG4-Related Disease Working Consortium:
Atsushi Kanno, Yoshihiro Okabe, Shinji Katsushima, Tetsuro Inokuma, Yukitaka Yamashita, Yoshitaka Nakai, Takayoshi Nishino, Kozo Kajimura, Mitsushige Shibatoge, Naoki Kanda, Akio Ido, Masaya Ohana, Ichiro Moriyama, Hiroshi Tatsuta, Kazuyoshi Matsumura, Keita Fujikawa, Norimoto Gotoh, Takanobu Tsutsumi, Masakazu Shimizu, Kazuya Setoh, Meiko Takahashi, Yasuharu Tabara, Jun Mimura, Takefumi Nakamura, Toshiyuki Kimura, Chiharu Kawanami

Affiliations

¹ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Internal Medicine 2, School of Medicine, Shinshu University, Matsumoto, Japan.
³ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan.
⁴ Department of Gastroenterology and Hepatology, Kyoto University, Kyoto, Japan.
⁵ Department of Gastroenterology and Hepatology Kansai Medical University, Hirakata, Japan.
⁶ Department of Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
⁷ Department of Endoscopy, Yokohama City University Hospital, Yokohama, Japan.
⁸ Department of Gastroenterology and Hepatology, Kitano Hospital, Osaka, Japan.
⁹ Department of Gastroenterology, Tokyo Takanawa Hospital, Tokyo, Japan.
¹⁰ Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Japan.
¹¹ Center for Gastroenterology, Teine-Keijinkai Hospital, Sapporo, Japan.
¹² Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
¹³ Center for Health Care and Human Sciences, University of Toyama, Toyama, Japan.
¹⁴ Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
¹⁵ Department of Gastroenterology, Kobe University Hospital, Kobe, Japan.
¹⁶ Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.
¹⁷ Department of Gastroenterology, Nagano Municipal Hospital, Tomitake, Japan.
¹⁸ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
¹⁹ Department of Gastroenterology, Second Teaching Hospital, Fujita Health University, Toyoake, Japan.
²⁰ First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
²¹ Department of Ophthalmology, National Hospital Organization Okayama Medical Center, Okayama, Japan.
²² First Department of Medicine, Wakayama Medical University, Wakayama, Japan.
²³ Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.
²⁴ Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
²⁵ Department of Internal Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan.
²⁶ Division of Rheumatology and Immunology, Nagahama City Hospital, Nagahama, Japan.
²⁷ Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
²⁸ Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan.
²⁹ Department of Rheumatology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
³⁰ Department of Ophthalmology, Kobe Kaisei Hospital, Kobe, Japan.
³¹ Department of Rheumatology and Clinical Immunology, Kyoto University, Kyoto, Japan.
³² Center for Health Safety and Environmental Management, Shinshu University, Matsumoto, Japan.
³³ Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: fumi@genome.med.kyoto-u.ac.jp.

PMID: 38229354
DOI: 10.1016/S2665-9913(19)30006-2

Abstract

Background: IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study.

Methods: We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined.

Findings: We identified the HLA-DRB1 (p=1·1×10^-11) and FCGR2B (p=2·0×10^-8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10^-14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10^-10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035).

Interpretation: Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders FUNDING: The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.