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Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis
Y. Kochi, Y. Kamatani, Y. Kondo, A. Suzuki, E. Kawakami, R. Hiwa, Y. Momozawa, M. Fujimoto, M. Jinnin, Y. Tanaka, T. Kanda, RG. Cooper, H. Chinoy, S. Rothwell, JA. Lamb, J. Vencovský, H. Mann, K. Ohmura, K. Myouzen, K. Ishigaki, R. Nakashima, Y....
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 1939-01-01 to 6 months ago
Health & Medicine (ProQuest)
from 1939-01-01 to 6 months ago
Family Health Database (ProQuest)
from 1939-01-01 to 6 months ago
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- Alleles MeSH
- Apoptosis genetics MeSH
- Asian People genetics MeSH
- Autoantibodies genetics MeSH
- Genome-Wide Association Study MeSH
- Dermatomyositis genetics MeSH
- Adult MeSH
- Genotype MeSH
- Genotyping Techniques MeSH
- Interferon-Induced Helicase, IFIH1 genetics immunology MeSH
- Intracellular Signaling Peptides and Proteins genetics MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Quantitative Trait Loci genetics MeSH
- NF-kappa B genetics MeSH
- Polymyositis genetics MeSH
- Protein Isoforms genetics MeSH
- Risk Factors MeSH
- Aged MeSH
- RNA Splicing genetics MeSH
- Signal Transduction genetics MeSH
- Case-Control Studies MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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 Dermatology Nagoya University Graduate School of Medicine Nagoya Japan
Department of Hematology and Immunology Kanazawa Medical University Ishikawa 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 Graduate School of Medicine The University of Tokyo Tokyo Japan
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
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
References provided by Crossref.org
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- $a Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis / $c Y. Kochi, Y. Kamatani, Y. Kondo, A. Suzuki, E. Kawakami, R. Hiwa, Y. Momozawa, M. Fujimoto, M. Jinnin, Y. Tanaka, T. Kanda, RG. Cooper, H. Chinoy, S. Rothwell, JA. Lamb, J. Vencovský, H. Mann, K. Ohmura, K. Myouzen, K. Ishigaki, R. Nakashima, Y. Hosono, H. Tsuboi, H. Kawasumi, Y. Iwasaki, H. Kajiyama, T. Horita, M. Ogawa-Momohara, A. Takamura, S. Tsunoda, J. Shimizu, K. Fujio, H. Amano, A. Mimori, A. Kawakami, H. Umehara, T. Takeuchi, H. Sano, Y. Muro, T. Atsumi, T. Mimura, Y. Kawaguchi, T. Mimori, A. Takahashi, M. Kubo, H. Kohsaka, T. Sumida, K. Yamamoto,
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- $a 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.
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