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.
- gene polymorphism
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Handling editor Tore K Kvien
Contributors YutK designed the study and drafted the manuscript. TS, HK and KY directed the Research Team for Autoimmune Diseases and revised the manuscript. YuM and MK performed the genotyping for GWAS. YutK, YoK and AtT analysed the GWAS data. YutK, EK and KI performed eQTL analysis and wPGSA. YutK and AS conducted the reporter assays and immunoprecipitation. KM performed apoptosis assays and immunofluorescence staining. RH, KO, ST and TM assayed anti-MDA5 Abs and performed immunoprecipitation analysis using the sera from patients with CADM. The following authors contributed to the Research Team for Autoimmune Diseases and its sample collection: YuyK, MF, MJ, YT, TK, RN, YH, HT, HidK, YI, HirK, TH, MO-M, AkT, ST, JS, KF, HA, AM, AK, HU, TT, YoM, TA, ToM, YaK, TsM, MK, HitK, TS and KY. MK directed the analysis of the BioBank samples. RGC, HC, JV and HM collected the European samples. SR and JAL analysed European CADM data.
Funding This work was supported by 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. This work was also supported by the BioBank Japan Project of the Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government.
Competing interests None declared.
Ethics approval All subjects were provided with written informed consent for participation in the study as approved by the ethical committee of each institutional review board.
Provenance and peer review Not commissioned; externally peer reviewed.