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.

Department of Allergy and Rheumatology Graduate School of Medicine the University of Tokyo Tokyo Japan

Department of Dermatology and Plastic Surgery Faculty of Life Sciences Kumamoto University Kumamoto Japan

Department of Dermatology Faculty of Medicine Institute of Medical Pharmaceutical and Health Sciences Kanazawa University Kanazawa Japan

Department of Dermatology Nagoya University Graduate School of Medicine Nagoya Japan

Department of Dermatology University of Tsukuba Ibaraki Japan

Department of Hematology and Immunology Kanazawa Medical University Ishikawa Japan

Department of Immunology and Rheumatology Unit of Advanced Preventive Medical Sciences Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan

Department of Internal Medicine and Rheumatology Juntendo University School of Medicine Tokyo Japan

Department of Internal Medicine Faculty of Medicine University of Tsukuba Tsukuba Japan

Department of Neurology and Clinical Neuroscience Yamaguchi University Graduate School of Medicine Ube Japan

Department of Neurology Graduate School of Medicine The University of Tokyo Tokyo Japan

Department of Rheumatology and Applied Immunology Faculty of Medicine Saitama Medical University Saitama Japan

Department of Rheumatology and Clinical Immunology Kyoto University Graduate School of Medicine Kyoto Japan

Department of Rheumatology Endocrinology and Nephrology Faculty of Medicine and Graduate School of Medicine Hokkaido University Sapporo Japan

Department of Rheumatology Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan

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

Division of Rheumatic Diseases National Center for Global Health and Medicine Tokyo Japan

Division of Rheumatology Department of Internal Medicine Hyogo College of Medicine Hyogo Japan

Division of Rheumatology Department of Internal Medicine Keio University School of Medicine Tokyo Japan

Institute of Rheumatology Charles University Prague Czech Republic

Institute of Rheumatology Tokyo Women's Medical University Tokyo Japan

Laboratory for Autoimmune Diseases RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory for Disease Systems Modeling RIKEN Center for Integrated Medical Sciences Yokohama Japan

Laboratory for Genotyping Development RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Yokohama Japan

MRC ARUK Institute for Ageing and Chronic Disease University of Liverpool Liverpool UK

Rheumatology Department Manchester Academic Health Science Centre Salford Royal NHS Foundation Trust Salford UK

The 1st Department of Internal Medicine University of Occupational and Environmental Health Kitakyushu Japan

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

References provided by Crossref.org

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation