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Splicing variant ofWDFY4augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis
Annals of the Rheumatic Diseases ( IF 20.3 ) Pub Date : 2018-01-13 , DOI: 10.1136/annrheumdis-2017-212149
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 , 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

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.

中文翻译:

WDFY4 的剪接变体增强 MDA5 信号和临床无肌病性皮肌炎的风险

目的 特发性炎症性肌病 (IIMs) 是一组异质性的罕见自身免疫性疾病,遗传和环境因素在其中发挥重要作用。为了确定 IIM 的遗传因素,包括多发性肌炎、皮肌炎 (DM) 和临床无肌病 DM (CADM),我们在亚洲人群中对 IIM 进行了第一次全基因组关联研究。方法 我们使用 576 名 IIM 患者和 6270 名对照受试者对 496 819 个单核苷酸多态性进行基因分型并测试其关联性。我们还通过使用公开数据集的计算机分析以及使用报告基因分析和细胞凋亡分析的体外分析检查了疾病相关变异的因果机制。结果 我们在 WDFY4 中发现了一个与 CADM 显着相关的变异(rs7919656;OR=3.87;P=1.5×10-8)。该变体对截短的 WDFY4 同种型 (tr-WDFY4) 具有顺式剪接数量性状基因座 (QTL) 效应,在风险等位基因中具有更高的表达。该变体的转表达 QTL 分析显示与 NF-κB 相关基因的表达呈正相关。此外,我们证明 WDFY4 和 tr-WDFY4 都与 TLR3、TLR4、TLR9 和 MDA5 等模式识别受体相互作用,并增强了这些受体对 NF-κB 的激活。WDFY4 同种型还在 tr-WDFY4 转染的细胞中更大程度地增强了 MDA5 诱导的细胞凋亡。结论 由于CADM以出现抗MDA5自身抗体和严重肺部炎症为特征,WDFY4变异体可能在CADM的发病机制中起关键作用。在风险等位基因中具有更高的表达。该变体的转表达 QTL 分析显示与 NF-κB 相关基因的表达呈正相关。此外,我们证明 WDFY4 和 tr-WDFY4 都与 TLR3、TLR4、TLR9 和 MDA5 等模式识别受体相互作用,并增强了这些受体对 NF-κB 的激活。WDFY4 同种型还在 tr-WDFY4 转染的细胞中更大程度地增强了 MDA5 诱导的细胞凋亡。结论 由于CADM以出现抗MDA5自身抗体和严重肺部炎症为特征,WDFY4变异体可能在CADM的发病机制中起关键作用。在风险等位基因中具有更高的表达。该变体的转表达 QTL 分析显示与 NF-κB 相关基因的表达呈正相关。此外,我们证明 WDFY4 和 tr-WDFY4 都与 TLR3、TLR4、TLR9 和 MDA5 等模式识别受体相互作用,并增强了这些受体对 NF-κB 的激活。WDFY4 同种型还在 tr-WDFY4 转染的细胞中更大程度地增强了 MDA5 诱导的细胞凋亡。结论 由于CADM以出现抗MDA5自身抗体和严重肺部炎症为特征,WDFY4变异体可能在CADM的发病机制中起关键作用。我们证明 WDFY4 和 tr-WDFY4 都与 TLR3、TLR4、TLR9 和 MDA5 等模式识别受体相互作用,并增强了这些受体对 NF-κB 的激活。WDFY4 同种型还在 tr-WDFY4 转染的细胞中更大程度地增强了 MDA5 诱导的细胞凋亡。结论 由于CADM以出现抗MDA5自身抗体和严重肺部炎症为特征,WDFY4变异体可能在CADM的发病机制中起关键作用。我们证明 WDFY4 和 tr-WDFY4 都与 TLR3、TLR4、TLR9 和 MDA5 等模式识别受体相互作用,并增强了这些受体对 NF-κB 的激活。WDFY4 同种型还在 tr-WDFY4 转染的细胞中更大程度地增强了 MDA5 诱导的细胞凋亡。结论 由于CADM以出现抗MDA5自身抗体和严重肺部炎症为特征,WDFY4变异体可能在CADM的发病机制中起关键作用。
更新日期:2018-01-13
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