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Ann Rheum Dis. 2018 Apr;77(4):602-611. doi: 10.1136/annrheumdis-2017-212149. Epub 2018 Jan 13.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

Author information

1
Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
2
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
3
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
4
Laboratory for Disease Systems Modeling, RIKEN Center for Integrated Medical Sciences, Yokohama, Japan.
5
Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
6
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
7
Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
8
Department of Dermatology, University of Tsukuba, Ibaraki, Japan.
9
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
10
The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
11
Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan.
12
MRC-ARUK Institute for Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
13
Division 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
Rheumatology Department, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Salford, UK.
15
The 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
Institute of Rheumatology, Charles University, Prague, Czech Republic.
17
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
18
Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
19
Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
20
Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
21
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
22
Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
23
Division of Rheumatology Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
24
Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
25
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
26
Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan.
27
Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
28
Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan.
29
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

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

PMID:
29331962
DOI:
10.1136/annrheumdis-2017-212149
[Indexed for MEDLINE]

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