Dysregulation of MS risk genes and pathways at distinct stages of disease

Srinivasan, Sundararajan; Dario, Marco Di; Russo, Alessandra; Menon, Ramesh; Brini, Elena; Romeo, Marzia; Sangalli, Francesca; Costa, Gloria Dalla; Rodegher, Mariaemma; Radaelli, Marta; Moiola, Lucia; Cantarella, Daniela; Medico, Enzo; Martino, Gianvito; Furlan, Roberto; Martinelli, Vittorio; Comı, Gıancarlo; Farina, Cinthia

doi:10.1212/nxi.0000000000000337

Cited by 28 publications

(31 citation statements)

References 24 publications

(34 reference statements)

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“…We have recently reported the selective dysregulation of MS risk genes in peripheral blood of MS patients 9 . Interestingly, some of them play a role in IFN-mediated pathways, e.g.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Srinivasan

Severa

Rizzo

et al. 2017

Sci Rep

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Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.

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“…We have recently reported the selective dysregulation of MS risk genes in peripheral blood of MS patients 9 . Interestingly, some of them play a role in IFN-mediated pathways, e.g.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Srinivasan

Severa

Rizzo

et al. 2017

Sci Rep

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“…Furthermore, they had not started any immunomodulatory therapy for MS yet. In the previous study, this dataset was used to validate the dysregulation of MS susceptibility genes (Srinivasan et al, 2017). The gene expression data of the three MS stages were thoroughly analyzed in our study to identify potential key candidate risk factors for MS.…”

Section: Methodsmentioning

confidence: 99%

Identification of key genes associated with multiple sclerosis based on gene expression data from peripheral blood mononuclear cells

Shang

Sun

Zhang

et al. 2020

PeerJ

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The aim of this study was to identify the potential key candidate genes of multiple sclerosis (MS) and uncover mechanisms in MS. We combined data from the microarray expression profile of three MS stages and performed bioinformatics analysis. Differentially expressed genes (DEGs) were identified among the distinct stages of MS and healthy controls, and a total of 349 shared DEGs were identified. Gene ontology (GO) and pathway enrichment analyses showed that the DEGs were significantly enriched in the biological processes (BPs) of purine-related metabolic processes and signaling, especially the common DEGs, which were enriched in some immunological processes. Most of the DEGs were enriched in signaling pathways associated with the immune system, some immune diseases and infectious disease pathways. Through a protein–protein interaction (PPI) network analysis and a gene expression regulatory network constructed with MS-related miRNAs, we confirmed FOS, TP53, VEGFA, JUN, HIF1A, RB1, PTGS2, CXCL8, OAS2, NFKBIA and OAS1 as candidate genes of MS. Furthermore , we explored the potential SNPs associated with MS by database mining. In conclusion, this study provides the identified genes, SNPs, biological processes, and cellular pathways associated with MS. The uncovered candidate genes may be potential biomarkers involved in the diagnosis and therapy of MS.

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“…Human peripheral blood mononuclear cell (PBMC) microarray datasets analyzed in this study were published in Srinivasan et al, 2017a;Srinivasan et al, 2017b) and deposited at EBI Array express database. The dataset was generated by Illumina Human Ref-8 v2 microarrays and contained PBMC transcriptomes of persons with MS (46 with clinically isolated syndromes, 52 with relapsing-remitting, 23 with primary-progressive, 21 with secondary-progressive disease) and 40 healthy controls.…”

Section: Blood Transcriptomementioning

confidence: 99%

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

Mechelli

Umeton

Srinivasan

et al. 2019

Preprint

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We exploited genetic information to assess the role of non-genetic factors in multifactorial diseases. To this aim we isolated candidate "interactomes" (i.e. groups of genes whose products are known to physically interact with environmental exposures and biological processes, plausibly relevant for disease pathogenesis) and analyzed nominal statistical evidence of association with genetic predisposition to multiple sclerosis (MS) and other inflammatory and non-inflammatory complex disorders. The interaction between genotype and Herpesviruses emerged as specific for MS, with Epstein Barr virus (EBV) showing higher levels of significance compared to Human Herpesvirus 8 (HHV8) and, more evidently, to cytomegalovirus (CMV). In accord with this result, when we classified the MS-associated genes contained in the interactomes into canonical pathways, the analysis converged towards biological functions of B cells, in particular the CD40 pathway. When we analyzed peripheral blood transcriptomes in persons with MS, we found a significant dysregulation of MS-associated genes belonging to the EBV interactome in primary progressive MS.This study indicates that the interaction between herpesviruses and predisposing genetic background is of causal significance in MS, and provides a mechanistic explanation for the long-recognized association between EBV and this condition.Many studies on environmental exposures in multifactorial diseases are correlative and associative in nature, hence the need to focus on causality and mechanism (Fischbach, 2018). Genome-wide association studies (GWAS) have the capability to inform about the causal relevance of associations between environmental exposures and disease. However, the difficulty in extracting value from the study of gene-environment interactions limits the interpretation of GWAS, therefore hindering what could be a virtuous 'genes-to-environment-to genes-again' iterative learning process (Visscher et al., 2017).In principle, Mendelian randomization allows to test for a causal effect of an epidemiological association. With this method, an environmental exposure is deemed to be plausibly causal if a genetic variant influencing the exposure is also directly associated with the disease (Davey Smith and Hemani, 2014). However, the influence of genetic variants on environmental exposures that associate with multifactorial diseases is far from being fully understood, particularly at the genome-wide level. More actionable data are available about the interaction, at the protein level, between human gene products and exposures. Furthermore, it has been shown that interacting disease-associated proteins have the propensity to influence each other in biologically relevant modules (Menche et al., 2015). Hence, in an approach akin to Mendelian randomization, we tested the possible causal significance of environmental exposures by measuring, at the genome-wide level, which genetic variants interacting with the exposure (i.e. influencing the exposure) were significantly enriched in MS GWAS data. ...

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Dysregulation of MS risk genes and pathways at distinct stages of disease

Cited by 28 publications

References 24 publications

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis

Identification of key genes associated with multiple sclerosis based on gene expression data from peripheral blood mononuclear cells

Significant enrichment of Herpesvirus interactors in GWAS data suggests causal inferences for the association between Epstein Barr virus and multiple sclerosis

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