Multiple Sclerosis: MicroRNA Expression Profiles Accurately Differentiate Patients with Relapsing-Remitting Disease from Healthy Controls

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, which is heterogenous with respect to clinical manifestations and response to therapy. Identification of biomarkers appears desirable for an improved diagnosis of MS as well as for monitoring of disease activity and treatment response. MicroRNAs (miRNAs) are short non-coding RNAs, which have been shown to have the potential to serve as biomarkers for different human diseases, most notably cancer. Here, we analyzed the expression profiles of 866 human miRNAs. In detail, we investigated the miRNA expression in blood cells of 20 patients with relapsing-remitting MS (RRMS) and 19 healthy controls using a human miRNA microarray and the Geniom Real Time Analyzer (GRTA) platform. We identified 165 miRNAs that were significantly up- or downregulated in patients with RRMS as compared to healthy controls. The best single miRNA marker, hsa-miR-145, allowed discriminating MS from controls with a specificity of 89.5%, a sensitivity of 90.0%, and an accuracy of 89.7%. A set of 48 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3%. While 43 of the 165 miRNAs deregulated in patients with MS have previously been related to other human diseases, the remaining 122 miRNAs are so far exclusively associated with MS. The implications of our study are twofold. The miRNA expression profiles in blood cells may serve as a biomarker for MS, and deregulation of miRNA expression may play a role in the pathogenesis of MS.

MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

“…As such, these miRNAs may be differentially expressed in other immunemediated diseases and have broader implications on CD4 T cell development and differentiation. It is well established that miRNAs play key roles in the development and function of Tregs (Gao et al, 2012;Josefowicz et al, 2012;Dooley et al, 2013), and differential expression of miRNAs have been found in patients with multiple sclerosis (Du et al, 2009;Keller et al, 2009;Otaegui et al, 2009;De Santis et al, 2010;Guerau-de-Arellano et al, 2011;Noorbakhsh et al, 2011;Jr OeF et al, 2012;Smith et al, 2012;Gandhi et al, 2013;Ridolfi et al, 2013;Søndergaard et al, 2013). To our knowledge none of the miRNAs identified in this study had been previously defined to play a role in Tregs.…”

“…While genetic studies have identified genes critical to the immune system as being potential risk factors (Baranzini et al, 2009b;De Jager et al, 2009;Beecham et al, 2013), many of the genetic contributors to this disease are unknown. An emerging area of interest in multiple sclerosis has been genetic regulation at the microRNA (miRNA) level (Du et al, 2009;Keller et al, 2009;Otaegui et al, 2009;De Santis et al, 2010;Guerau-de-Arellano et al, 2011;Noorbakhsh et al, 2011;Jr OeF et al, 2012;Smith et al, 2012;Gandhi et al, 2013;Ridolfi et al, 2013;Søndergaard et al, 2013). MiRNAs are small, non-coding RNA that regulate gene expression and, thus, modify cellular pathways and disease processes (Ambros, 2004;Bartel, 2004).…”

Altered expression of miR‐17‐5p in CD4+ lymphocytes of relapsing–remitting multiple sclerosis patients

“…Recently Otaegui et al [30] reported differential miRNA expression in PBMC from MS patients during remission and relapses. Another recent study described diverse miRNA expression profiles in whole blood cells of MS patients compared with healthy controls [31]. However, nothing is known about miRNA expression in various cell subpopulations and their importance during the differentiation and activation of lymphocytes in MS.…”

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

“…In 2009, a study defined hsa-miR-145 as a biomarker of MS with a specificity of 95%, a sensitivity of 97.6%, and an accuracy of 96.3% [45]. This microRNA was found to induce rearrangement of the actin cytoskeleton and nuclear rotation when overexpressed, affecting vital cellular functions such as cell migration, division and polarity.…”