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

Yuta Kochi, Yoichiro Kamatani, Yuya Kondo, Akari Suzuki, Eiryo Kawakami, Ryosuke Hiwa, Yukihide Momozawa, Manabu Fujimoto, Masatoshi Jinnin, Yoshiya Tanaka, Takashi Kanda, Robert G. Cooper, Hector Chinoy, Simon Rothwell, Janine A. Lamb, Jiří Vencovský, Heřman Mann, Koichiro Ohmura, Keiko Myouzen, Kazuyoshi Ishigaki & 28 others Ran Nakashima, Yuji Hosono, Hiroto Tsuboi, Hidenaga Kawasumi, Yukiko Iwasaki, Hiroshi Kajiyama, Tetsuya Horita, Mariko Ogawa-Momohara, Akito Takamura, Shinichiro Tsunoda, Jun Shimizu, Keishi Fujio, Hirofumi Amano, Akio Mimori, Atsushi Kawakami, Hisanori Umehara, Tsutomu Takeuchi, Hajime Sano, Yoshinao Muro, Tatsuya Atsumi, Toshihide Mimura, Yasushi Kawaguchi, Tsuneyo Mimori, Atsushi Takahashi, Michiaki Kubo, Hitoshi Kohsaka, Takayuki Sumida, Kazuhiko Yamamoto

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)602-611
Number of pages10
JournalAnnals of the Rheumatic Diseases
Volume77
Issue number4
DOIs
Publication statusPublished - 01-04-2018

Fingerprint

Myositis
Assays
Genes
Association reactions
Apoptosis
Pattern Recognition Receptors
Quantitative Trait Loci
Polymorphism
Autoantibodies
Protein Isoforms
Nucleotides
Chemical activation
Dermatomyositis
Genome-Wide Association Study
Rare Diseases
Computer Simulation
Autoimmune Diseases
Single Nucleotide Polymorphism
Pneumonia
Alleles

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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, Hector ; 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. / Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis. In: Annals of the Rheumatic Diseases. 2018 ; Vol. 77, No. 4. pp. 602-611.
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title = "Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis",
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.",
author = "Yuta Kochi and Yoichiro Kamatani and Yuya Kondo and Akari Suzuki and Eiryo Kawakami and Ryosuke Hiwa and Yukihide Momozawa and Manabu Fujimoto and Masatoshi Jinnin and Yoshiya Tanaka and Takashi Kanda and Cooper, {Robert G.} and Hector Chinoy and Simon Rothwell and Lamb, {Janine A.} and Jiř{\'i} Vencovsk{\'y} and Heřman Mann and Koichiro Ohmura and Keiko Myouzen and Kazuyoshi Ishigaki and Ran Nakashima and Yuji Hosono and Hiroto Tsuboi and Hidenaga Kawasumi and Yukiko Iwasaki and Hiroshi Kajiyama and Tetsuya Horita and Mariko Ogawa-Momohara and Akito Takamura and Shinichiro Tsunoda and Jun Shimizu and Keishi Fujio and Hirofumi Amano and Akio Mimori and Atsushi Kawakami and Hisanori Umehara and Tsutomu Takeuchi and Hajime Sano and Yoshinao Muro and Tatsuya Atsumi and Toshihide Mimura and Yasushi Kawaguchi and Tsuneyo Mimori and Atsushi Takahashi and Michiaki Kubo and Hitoshi Kohsaka and Takayuki Sumida and Kazuhiko Yamamoto",
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Kochi, Y, Kamatani, Y, Kondo, Y, Suzuki, A, Kawakami, E, Hiwa, R, Momozawa, Y, Fujimoto, M, Jinnin, M, Tanaka, Y, Kanda, T, Cooper, RG, Chinoy, H, Rothwell, S, Lamb, JA, Vencovský, J, Mann, H, Ohmura, K, Myouzen, K, Ishigaki, K, Nakashima, R, Hosono, Y, Tsuboi, H, Kawasumi, H, Iwasaki, Y, Kajiyama, H, Horita, T, Ogawa-Momohara, M, Takamura, A, Tsunoda, S, Shimizu, J, Fujio, K, Amano, H, Mimori, A, Kawakami, A, Umehara, H, Takeuchi, T, Sano, H, Muro, Y, Atsumi, T, Mimura, T, Kawaguchi, Y, Mimori, T, Takahashi, A, Kubo, M, Kohsaka, H, Sumida, T & Yamamoto, K 2018, 'Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis', Annals of the Rheumatic Diseases, vol. 77, no. 4, pp. 602-611. https://doi.org/10.1136/annrheumdis-2017-212149

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis. / 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, Hector; 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.

In: Annals of the Rheumatic Diseases, Vol. 77, No. 4, 01.04.2018, p. 602-611.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis

AU - Kochi, Yuta

AU - Kamatani, Yoichiro

AU - Kondo, Yuya

AU - Suzuki, Akari

AU - Kawakami, Eiryo

AU - Hiwa, Ryosuke

AU - Momozawa, Yukihide

AU - Fujimoto, Manabu

AU - Jinnin, Masatoshi

AU - Tanaka, Yoshiya

AU - Kanda, Takashi

AU - Cooper, Robert G.

AU - Chinoy, Hector

AU - Rothwell, Simon

AU - Lamb, Janine A.

AU - Vencovský, Jiří

AU - Mann, Heřman

AU - Ohmura, Koichiro

AU - Myouzen, Keiko

AU - Ishigaki, Kazuyoshi

AU - Nakashima, Ran

AU - Hosono, Yuji

AU - Tsuboi, Hiroto

AU - Kawasumi, Hidenaga

AU - Iwasaki, Yukiko

AU - Kajiyama, Hiroshi

AU - Horita, Tetsuya

AU - Ogawa-Momohara, Mariko

AU - Takamura, Akito

AU - Tsunoda, Shinichiro

AU - Shimizu, Jun

AU - Fujio, Keishi

AU - Amano, Hirofumi

AU - Mimori, Akio

AU - Kawakami, Atsushi

AU - Umehara, Hisanori

AU - Takeuchi, Tsutomu

AU - Sano, Hajime

AU - Muro, Yoshinao

AU - Atsumi, Tatsuya

AU - Mimura, Toshihide

AU - Kawaguchi, Yasushi

AU - Mimori, Tsuneyo

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Kohsaka, Hitoshi

AU - Sumida, Takayuki

AU - Yamamoto, Kazuhiko

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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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U2 - 10.1136/annrheumdis-2017-212149

DO - 10.1136/annrheumdis-2017-212149

M3 - Article

VL - 77

SP - 602

EP - 611

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 4

ER -