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

Abstract

Objectives Idiopathic inflammatory myopathies (IIM) 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 (PM), dermatomyositis (DM), and clinically amyopathic DM (CADM), we performed the first genome-wide association study (GWAS) for IIM in an Asian population.Methods We genotyped and tested 496,819 SNPs for association using 576 IIM patients and 6,270 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; odds ratio (OR)=3.87; P=1.5×10 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 characterized by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Targeted capture sequencing identifies novel genetic variations in Chinese patients with idiopathic inflammatory myopathies

“…in a Japanese population, no significant association signal ( P < 5 × 10 −8 ) within HLA region was found in any of total IIM, PM or DM patients compared to healthy controls . Instead, an intronic SNP of WDFY4 (rs7919656) was found to be significantly associated with clinically amyopathic DM . The lack of association to the HLA region in the Kochi study may be explained by the patient distribution in their study cohorts.…”

“…Interestingly, despite that a number of studies confirmed HLA alleles as the strongest genetic risk factor in Western populations, in a recent IIM GWAS conducted by Kochi et al. in a Japanese population, no significant association signal ( P < 5 × 10 −8 ) within HLA region was found in any of total IIM, PM or DM patients compared to healthy controls . Instead, an intronic SNP of WDFY4 (rs7919656) was found to be significantly associated with clinically amyopathic DM .…”

Natural Autoantibodies in Chronic Pulmonary Diseases

“…Another example is the anti-melanoma differentiation-associated gene 5 (MDA5) autoAb that is used to diagnose progressive interstitial lung disease with poor prognosis among chronic fibrosing IIPs [17]. Although some reports support the hypothesis that such autoAbs are pathogenic [18,19], in the absence of direct proof, these autoAbs are thought to represent natural autoantibodies in chronic fibrosing IIPs.…”

Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility

“…Interestingly, it was later found to be under strong selection in the past 2000 years in the UK (Field et al, ). Several recent studies indicate the involvement of this gene in autophagy (Yuan et al, ), NF‐κB signaling (Kochi et al, ), and cross‐presentation in response to viral and tumor antigens (Theisen et al, ). This process highlights the significance of genetic studies in opening a window to understanding the functions of genes, although it may take years of functional characterizations.…”