Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis
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Published:2018-01-13
Issue:4
Volume:77
Page:602-611
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ISSN:0003-4967
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Container-title:Annals of the Rheumatic Diseases
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language:en
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Short-container-title:Ann Rheum Dis
Author:
Kochi Yuta, Kamatani Yoichiro, Kondo Yuya, Suzuki Akari, Kawakami Eiryo, Hiwa Ryosuke, Momozawa Yukihide, Fujimoto Manabu, Jinnin Masatoshi, Tanaka Yoshiya, Kanda Takashi, Cooper Robert G, Chinoy HectorORCID, Rothwell Simon, Lamb Janine A, Vencovský Jiří, Mann Heřman, Ohmura Koichiro, Myouzen Keiko, Ishigaki Kazuyoshi, Nakashima Ran, Hosono Yuji, Tsuboi Hiroto, Kawasumi Hidenaga, Iwasaki Yukiko, Kajiyama Hiroshi, Horita Tetsuya, Ogawa-Momohara Mariko, Takamura Akito, Tsunoda Shinichiro, Shimizu Jun, Fujio Keishi, Amano Hirofumi, Mimori Akio, Kawakami Atsushi, Umehara Hisanori, Takeuchi Tsutomu, Sano Hajime, Muro Yoshinao, Atsumi Tatsuya, Mimura Toshihide, Kawaguchi Yasushi, Mimori Tsuneyo, Takahashi Atsushi, Kubo Michiaki, Kohsaka Hitoshi, Sumida Takayuki, Yamamoto Kazuhiko
Abstract
ObjectivesIdiopathic 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.MethodsWe 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.ResultsWe 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.ConclusionsAs 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.
Funder
The BioBank Japan Project of the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. 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.
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
Cited by
50 articles.
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