Abstract
We aim to identify differentially expressed genes (DEGs) and its pathways associated with clinical activity of relapsing–remitting Multiple Sclerosis (RRMS). We screened DEG in blood samples from patients with clinically stable or active RRMS (≥2 relapses or increase in ≥1 point in the EDSS (due to relapses) in 2 years follow-up), and healthy controls using DNA arrays. The DEGs identified were validated by RT-PCR in a prospective cohort of MS patients. We used Gene Ontology (GO) analysis for identifying the associated pathways and Jaspar database for identifying the associated transcriptions factors. We identified 45 DEG between the three groups (stable RRMS, active RRMS and control), being 14 of them significantly different between stable and active RRMS. We validated 14 out of the 45 DEG in the second cohort, eight out of the 14 being differentially expressed between active and stable patients (ARHGEF7, CASP2, DOCK10, DSP, ITPR1, KLDHC5, RBBP4, SYTL2). We found an overrepresentation of several pathways associated with lymphocyte activation. The analysis of regulatory networks identified the gene triplet of Dedicator of Cytokinesis-10 (DOCK10) – Caspase-2 (CASP2) - Synaptotagmin-like 2 (SYTL2) as being co-regulated by common transcription factors, pointing to lymphocyte activation pathways associated with disease activity. We describe the triplet DOCK10 - CASP2 - SYTL2 as associated with the clinical activity of RRMS that suggest the role of lymphocyte activation, type 1 interferon and MAPkinase pathways in driving the presence of new relapses and disability accumulation.
Highlights
We aim to identify differentially expressed genes (DEGs) and its pathways associated with clinical activity of relapsing–remitting Multiple Sclerosis (RRMS)
RNA extracted from whole blood was analyzed using the HG-U133 Plus 2.0 DNA array (Affymetrix), obtaining 14,705 of the 54,675 available probes which fulfilled the criteria for analysis
To validate the DEGs associated with clinical activity in relapsing-remitting MS (RRMS), we analyzed the expression of the DEGs by RT-PCR in a second independent cohort of Multiple sclerosis (MS) patients
Summary
We aim to identify differentially expressed genes (DEGs) and its pathways associated with clinical activity of relapsing–remitting Multiple Sclerosis (RRMS). To achieve an accurate prognosis during the early or mid-stages of the disease, and to monitor both disease course and the response to therapy, it is essential to identify clinical or biological markers that can serve as surrogate end-points of the phenotype [1,2,3,4] Such biomarkers would greatly facilitate the design and monitoring of clinical trials to test new disease-modifying drugs by identifying the most appropriate patient subgroups for a specific therapy of interest. The underlying pathogenesis of RRMS activity is dependent on the presence of new inflammatory plaques within the brain parenchyma, as a result of the activation of the immune system At present, it is not well known which pathways are activated during relapses and which ones are critical for defining a more active disease activity [5]. At present none of such genes have been validated as a known biomarker of disease activity in MS and the pathways driving a more active disease are not well known [2, 5]
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