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 NakazawaHideyuki 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, 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

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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.

Original languageEnglish
Pages (from-to)e14-e22
JournalThe Lancet Rheumatology
Volume1
Issue number1
DOIs
Publication statusPublished - Sep 2019

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology

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    Terao, C., Ota, M., Iwasaki, T., Shiokawa, M., Kawaguchi, S., Kuriyama, K., Kawaguchi, T., Kodama, Y., Yamaguchi, I., Uchida, K., Higasa, K., Yamamoto, M., Kubota, K., Yazumi, S., Hirano, K., Masaki, Y., Maguchi, H., Origuchi, T., Matsui, S., ... Kawanami, C. (2019). IgG4-related disease in the Japanese population: a genome-wide association study. The Lancet Rheumatology, 1(1), e14-e22. https://doi.org/10.1016/S2665-9913(19)30006-2