Background Micro-RNA (miRNA) are small noncoding RNAs that regulate gene expression at a posttranslational level. Alteration of miRNA expression with a diagnostic and prognostic character has been described not only in oncogenesis but also in chronic inflammatory diseases such as RA, SLE, Sjögren’s syndrome or chronic inflammatory bowel disease. In this context, no investigations in vasculitides have been described (1).
Objectives To characterize for the first time miRNA profiles associated with GPA and to identify new miRNA targets of potential pathophysiological relevance.
Methods Nasal tissue samples of 20 GPA-patients, 10 disease controls (CRS: chronic rhinosinusitis with polyps) and of 10 healthy controls (HC) were selected for genome-wide miRNA screening using an Affymetrix miRNA-microarray displaying 847 human miRNAs. Significantly differentially expressed miRNAs were identified by Mann-Whitney U-test; fold changes were based on the ratios of the medians of each experimental group. Visualization of the results was generated using TIBCO Spotfire. Putative miRNA targets were predicted by combining three different computational methods: (i) PubMed search, (ii) Tarbase 5.0 (Diana labs), an algorithm for experimentally validated targets and (iii) microRNA Data Integration Portal (mirDIP), a tool combining up to 12 different algorithms for target prediction.
Results 1. GPA specific miRNA expression pattern: From 847 human miRNA screened, 99 were found to be differentially expressed when comparing GPA to HC (p≤0.05). At a cut-off level of a twofold up- or downregulation, 25 miRNAs remained. Of those 25 miRNAs, 24 displayed a GPA-specific expression pattern. Furthermore, 3 miRNAs (unregulated: miR-1228 and -532-5p: downregulated: miR-708 in GPA) were inversely regulated in GPA compared to CRS.
2. Target prediction revealed previously experimentally validated targets involved in T- and B-cell, in fibroblast and osteoblast proliferation and differentiation, apoptosis, hypoxia, angiogenesis and cellular adhesion. These are known pathways in the pathogenesis of GPA. Potential targets also include proteinase-3, the specific GPA autoantigen, and lysosomal membrane protein-2, only recently described as an alternative autoantigen in GPA.
Conclusions This explorative survey for the first time documents disease associated miRNA profiles in nasal tissue samples of GPA patients when compared to healthy individuals and disease controls. Target prediction of these 24 GPA specific miRNAs suggests involvement in known pathological pathways of GPA. Considering the promising diagnostic, prognostic and therapeutical applications of miRNAs in other diseases (2), validating the clinical relevance of the presented data will help to understand the GPA on a molecular level, which represents a key element in developing new therapies.
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Disclosure of Interest None Declared
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