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Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis
  1. Yuta Kochi1,
  2. Yoichiro Kamatani2,
  3. Yuya Kondo3,
  4. Akari Suzuki1,
  5. Eiryo Kawakami4,
  6. Ryosuke Hiwa5,
  7. Yukihide Momozawa6,
  8. Manabu Fujimoto7,8,
  9. Masatoshi Jinnin9,
  10. Yoshiya Tanaka10,
  11. Takashi Kanda11,
  12. Robert G Cooper12,13,
  13. Hector Chinoy14,15,
  14. Simon Rothwell15,
  15. Janine A Lamb13,
  16. Jiří Vencovský16,
  17. Heřman Mann16,
  18. Koichiro Ohmura5,
  19. Keiko Myouzen1,
  20. Kazuyoshi Ishigaki2,
  21. Ran Nakashima5,
  22. Yuji Hosono5,
  23. Hiroto Tsuboi3,
  24. Hidenaga Kawasumi17,
  25. Yukiko Iwasaki18,
  26. Hiroshi Kajiyama19,
  27. Tetsuya Horita20,
  28. Mariko Ogawa-Momohara21,
  29. Akito Takamura22,
  30. Shinichiro Tsunoda23,
  31. Jun Shimizu24,
  32. Keishi Fujio18,
  33. Hirofumi Amano25,
  34. Akio Mimori26,
  35. Atsushi Kawakami27,
  36. Hisanori Umehara28,
  37. Tsutomu Takeuchi29,
  38. Hajime Sano23,
  39. Yoshinao Muro21,
  40. Tatsuya Atsumi20,
  41. Toshihide Mimura19,
  42. Yasushi Kawaguchi17,
  43. Tsuneyo Mimori5,
  44. Atsushi Takahashi2,
  45. Michiaki Kubo6,
  46. Hitoshi Kohsaka22,
  47. Takayuki Sumida3,
  48. Kazuhiko Yamamoto1,18
  1. 1Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  2. 2Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  3. 3Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  4. 4Laboratory for Disease Systems Modeling, RIKEN Center for Integrated Medical Sciences, Yokohama, Japan
  5. 5Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
  6. 6Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  7. 7Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
  8. 8Department of Dermatology, University of Tsukuba, Ibaraki, Japan
  9. 9Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
  10. 10The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  11. 11Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan
  12. 12MRC-ARUK Institute for Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
  13. 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
  14. 14Rheumatology Department, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK
  15. 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
  16. 16Institute of Rheumatology, Charles University, Prague, Czech Republic
  17. 17Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan
  18. 18Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
  19. 19Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
  20. 20Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  21. 21Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  22. 22Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  23. 23Division of Rheumatology Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
  24. 24Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  25. 25Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan
  26. 26Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan
  27. 27Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  28. 28Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan
  29. 29Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  1. Correspondence to Dr Yuta Kochi, Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Tsurumi-Ku, Yokohama 230-0045, Japan; yuta.kochi{at}riken.jp

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.

  • dermatomyositis
  • polymyositis
  • gene polymorphism
  • autoimmunity

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors YutK designed the study and drafted the manuscript. TS, HK and KY directed the Research Team for Autoimmune Diseases and revised the manuscript. YuM and MK performed the genotyping for GWAS. YutK, YoK and AtT analysed the GWAS data. YutK, EK and KI performed eQTL analysis and wPGSA. YutK and AS conducted the reporter assays and immunoprecipitation. KM performed apoptosis assays and immunofluorescence staining. RH, KO, ST and TM assayed anti-MDA5 Abs and performed immunoprecipitation analysis using the sera from patients with CADM. The following authors contributed to the Research Team for Autoimmune Diseases and its sample collection: YuyK, MF, MJ, YT, TK, RN, YH, HT, HidK, YI, HirK, TH, MO-M, AkT, ST, JS, KF, HA, AM, AK, HU, TT, YoM, TA, ToM, YaK, TsM, MK, HitK, TS and KY. MK directed the analysis of the BioBank samples. RGC, HC, JV and HM collected the European samples. SR and JAL analysed European CADM data.

  • 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.

  • Competing interests None declared.

  • Ethics approval All subjects were provided with written informed consent for participation in the study as approved by the ethical committee of each institutional review board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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