@article{79bada53484b4072a3b5864a0f18dfef,
title = "Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis",
abstract = "Objectives Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. Methods We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. Results We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10 -8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-ΚB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-ΚB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. Conclusions As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.",
keywords = "autoimmunity, dermatomyositis, gene polymorphism, polymyositis",
author = "Yuta Kochi and Yoichiro Kamatani and Yuya Kondo and Akari Suzuki and Eiryo Kawakami and Ryosuke Hiwa and Yukihide Momozawa and Manabu Fujimoto and Masatoshi Jinnin and Yoshiya Tanaka and Takashi Kanda and Cooper, {Robert G.} and Hector Chinoy and Simon Rothwell and Lamb, {Janine A.} and Ji{\v r}{\'i} Vencovsk{\'y} and He{\v r}man Mann and Koichiro Ohmura and Keiko Myouzen and Kazuyoshi Ishigaki and Ran Nakashima and Yuji Hosono and Hiroto Tsuboi and Hidenaga Kawasumi and Yukiko Iwasaki and Hiroshi Kajiyama and Tetsuya Horita and Mariko Ogawa-Momohara and Akito Takamura and Shinichiro Tsunoda and Jun Shimizu and Keishi Fujio and Hirofumi Amano and Akio Mimori and Atsushi Kawakami and Hisanori Umehara and Tsutomu Takeuchi and Hajime Sano and Yoshinao Muro and Tatsuya Atsumi and Toshihide Mimura and Yasushi Kawaguchi and Tsuneyo Mimori and Atsushi Takahashi and Michiaki Kubo and Hitoshi Kohsaka and Takayuki Sumida and Kazuhiko Yamamoto",
note = "Funding Information: 1Laboratory for Autoimmune diseases, rIKEn Center for Integrative Medical Sciences, Yokohama, Japan 2Laboratory for Statistical Analysis, rIKEn Center for Integrative Medical Sciences, Yokohama, Japan 3department of Internal Medicine, Faculty of Medicine, University of tsukuba, tsukuba, Japan 4Laboratory for disease Systems Modeling, rIKEn Center for Integrated Medical Sciences, Yokohama, Japan 5department of rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan 6Laboratory for Genotyping development, rIKEn Center for Integrative Medical Sciences, Yokohama, Japan 7department of dermatology, Faculty of Medicine, Institute of Medical, pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan 8department of dermatology, University of tsukuba, Ibaraki, Japan 9department of dermatology and plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan 10the First department of Internal Medicine, University of occupational and Environmental Health, Kitakyushu, Japan 11department of neurology and Clinical neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan 12MrC-ArUK Institute for Ageing and Chronic disease, University of Liverpool, Liverpool, UK 13division of population Health, Health Services research and primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, Centre for Integrated Genomic Medical research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK 14rheumatology department, Manchester Academic Health Science Centre, Salford royal nHS Foundation trust, Salford, UK 15the national Institute for Health research Manchester Musculoskeletal Biomedical research Unit, Central Manchester University Hospitals nHS Foundation trust, Manchester Academic Health Science Centre, the University of Manchester, Manchester, UK 16Institute of rheumatology, Charles University, prague, Czech republic 17Institute of rheumatology, tokyo Women{\textquoteright}s Medical University, tokyo, Japan 18department of Allergy and rheumatology, Graduate School of Medicine, the University of tokyo, tokyo, Japan 19department of rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan 20department of rheumatology, Endocrinology and nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 21department of dermatology, nagoya University Graduate School of Medicine, nagoya, Japan 22department of rheumatology, Graduate School of Medical and dental Sciences, tokyo Medical and dental University, tokyo, Japan 23division of rheumatology department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan 24department of neurology, Graduate School of Medicine, the University of tokyo, tokyo, Japan 25department of Internal Medicine and rheumatology, Juntendo University School of Medicine, tokyo, Japan 26division of rheumatic diseases, national Center for Global Health and Medicine, tokyo, Japan 27department of Immunology and rheumatology, Unit of Advanced preventive Medical Sciences, nagasaki University Graduate School of Biomedical Sciences, nagasaki, Japan 28department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan 29division of rheumatology, department of Internal Medicine, Keio University School of Medicine, tokyo, Japan Acknowledgements We would like to thank K Kobayashi and M Abe for their technical assistance and dr r Yamada and dr Y okada for their advice at rIKEn. We would also like to thank dr F W Miller at the US national Institutes of Health, who established the MYoGEn consortium, for arranging the collaboration. We thank dr K Miyake at the University of tokyo, dr H Kato and dr t Fujita at Kyoto University for providing technical advice and reagents. Funding Information: Funding this work was supported by the Health and Labour Sciences research Grants for research on intractable diseases (the research team for Autoimmune diseases) from the Ministry of Health, Labour and Welfare of Japan. this work was also supported by the BioBank Japan project of the Ministry of Education, Culture, Sports, Sciences and technology of the Japanese government. Publisher Copyright: {\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",
year = "2018",
month = apr,
doi = "10.1136/annrheumdis-2017-212149",
language = "English",
volume = "77",
pages = "602--611",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "4",
}