| 論文種別 | 原著(症例報告除く) |
| 言語種別 | 英語 |
| 査読の有無 | その他(不明) |
| 表題 | IgG4-related disease in the Japanese population: a whole-genome sequencing study. |
| 掲載誌名 | 正式名：The Lancet. Rheumatology 略 称：Lancet Rheumatol ISSNコード：26659913/26659913 |
| 掲載区分 | 国外 |
| 巻・号・頁 | 8(1),pp.e11-e22 |
| 著者・共著者 | Yuxun Oswald Zhang, Takeshi Iwasaki, Takahisa Kawaguchi, Hiroki Takahashi, Shuji Kawaguchi, Atsushi Kanno, Izumi Yamaguchi, Kensuke Kubota, Hiroaki Dobashi, Masao Nagasaki, Motohisa Yamamoto, Meiko Takahashi, Masakazu Shimizu, Tsukasa Ikeura, Shoko Matsui, Masatoshi Kanda, Koki Nakamura, Kensuke Yokoyama, Atsushi Azumi, Yasufumi Masaki, Ichiro Mizushima, Yusuke Kurita, Hiroshi Seno, Tomoki Origuchi, Shujiro Yazumi, Kenji Hirano, Atsushi Masamune, Nobumasa Mizuno, Hiromi Shimada, Masafumi Moriyama, Yasuki Hori, Yuzo Kodama, Takako Saeki, Toshifumi Kin, Chiharu Kawanami, Masanori Asada, Takashi Akamizu, Akira Nakamura, Koichi Oshima, Yoshiya Tanaka, Hajime Yoshifuji, Terumi Kamisawa, Toshiyuki Kimura, Hisanori Umehara, Hideki Ishikawa, Tsutomu Chiba, Kazuichi Okazaki, Tsuneyo Mimori, Seiji Nakamura, Mitsuhiro Kawano, Fumihiko Matsuda, |
| 発行年月 | 2026/01 |
| 概要 | BACKGROUND:IgG4-related disease is a rare autoimmune disorder characterised by tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, elevated serum IgG4 concentrations, and increased risk of tumour complications. Previous genetic studies have implicated FCGR2B and HLA loci in susceptibility to IgG4-related disease; however, most relied on microarray-based genotyping and imputation, which have limited resolution in highly polymorphic and structurally complex regions. This study aimed to investigate genetic susceptibility to IgG4-related disease using comprehensive genomic variant analysis, including low-frequency and structural variants not readily captured by microarrays.METHODS:We conducted a genome-wide association study using whole-genome sequencing data in a two-set, subtype-stratified case-control design in the Japanese population. Set 1 included samples (cases) from patients with IgG4-related disease from 50 hospitals across Japan participating in the Japanese IgG4-related disease Working Consortium (recruited between Oct 27, 2008, and March 3, 2016) and previously sequenced Japanese population control samples. Set 2 included samples (cases) from patients with IgG4-related disease from eight hospitals of the Consortium (recruited between Aug 12, 2021, and Dec 20, 2023) and previously sequenced healthy individuals residing in the Tokyo metropolitan area (controls). No specific inclusion or exclusion criteria were applied to either cases and controls. We used whole-genome sequencing at depths of 15× or 30× using HiSeqX and NovaSeq platforms (Illumina; San Diego, CA, USA) to enable the inclusion of previously uncaptured single nucleotide polymorphisms and direct analysis of HLA amino acid residues. We investigated complement component 4 copy number variations using short-read sequencing data and established read-depth-based typing methods. People with lived experience of IgG4-related disease were not involved in the study.FINDINGS:This whole-genome sequencing study comprised of 2 sets. Set 1 included 646 patient samples (172 [26·6%] were female, 474 [73·4%] were male, and the mean age was 64·4 years [SD 11·4]) and 2254 population controls (1348 [59·8%] were female and 906 [40·2%] were male). Set 2 included 223 patient samples (78 [35·0%] were female, 145 [65·0%] were male, and the mean age was 63·5 years [10·9]) and 405 population controls (65 [16·0%] were female and 340 [84·0%] were male). All individuals were of Hondo Japanese ancestry. The average IgG4 concentration at diagnosis was 653·1 mg/dL (SD 596·3) in Set 1 and 543·5 mg/dL (603·5) in Set 2. We validated the FCGR2B (p=9·8 × 10-11) region as the susceptibility locus for IgG4-related disease. PTCH1 (p=3·8 × 10-8) and long non-coding RNA LOC102724227 were found to be specific susceptibility loci for Mikulicz's disease. We also confirmed the association between the HLA amino acid residue DRB1-GB-7 (p=1·1 × 10-19) with IgG4-related disease and identified two additional residues, A-GA2-9 (p=4·1 × 10-6) and DQB1-GB-82 (p=4·7 × 10-9), that were significantly associated with IgG4-related disease. In the joint-association analysis of complement component 4 copy number variation, C4A showed a protective association with IgG4-related disease (β=-0·127, p=7·9 × 10-3), whereas C4B was associated with an increased risk (β=0·151, p=1·9 × 10-2). A low level of linkage disequilibrium (r2<0·15) was observed between the C4A and C4B alleles and the identified HLA amino acid residues in the main island Japanese population.INTERPRETATION:C4 copy number variation, in addition to HLA and FCGR2B, was found to be a distinct genetic factor associated with IgG4-related disease susceptibility, illustrating the complex polygenic nature of the disease. Furthermore, the identification of PTCH1 and the long non-coding RNA LOC102724227 as Mikulicz's disease-specific susceptibility loci suggests that genetic heterogeneity might underlie the clinical diversity of IgG4-related disease, particularly with respect to the affected organs.FUNDING:The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, the Kyoto University Grant for Top Global University Japan Project, and the Kyoto University Division of Graduate Studies SPRING Program. |
| DOI | 10.1016/S2665-9913(25)00195-X |
| PMID | 41197642 |