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dc.contributor.authorGil-Varea, E.-
dc.contributor.authorSpataro, N.-
dc.contributor.authorVillar, L.M.-
dc.contributor.authorTejeda-Velarde, A.-
dc.contributor.authorMidaglia, L.-
dc.contributor.authorMatesanz, F.-
dc.contributor.authorMalhotra, S.-
dc.contributor.authorEixarch, H.-
dc.contributor.authorPatsopoulos, N.-
dc.contributor.authorFernández, Óscar-
dc.contributor.authorOliver-Martos, Begoña-
dc.contributor.authorSáiz, Albert-
dc.contributor.authorLlufriu, S.-
dc.contributor.authorRamió-Torrentà, Lluís-
dc.contributor.authorQuintana, E.-
dc.contributor.authorIzquierdo, G.-
dc.contributor.authorAlcina, Antonio-
dc.contributor.authorBosch, E.-
dc.contributor.authorNavarro, A.-
dc.contributor.authorMontalbán, Xavier-
dc.contributor.authorComabella, Manuel-
dc.date.accessioned2020-07-16T09:40:22Z-
dc.date.available2020-07-16T09:40:22Z-
dc.date.issued2020-
dc.identifierdoi: 10.1002/humu.24016-
dc.identifierissn: 1059-7794-
dc.identifiere-issn: 1098-1004-
dc.identifier.citationHuman Mutation (2020)-
dc.identifier.urihttp://hdl.handle.net/10261/216748-
dc.description.abstractAlthough genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-β compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.-
dc.description.sponsorshipThis work was supported by grants from the Fondo de Investigación Sanitaria (FIS; grant number PI12/02229; Ministry of Science and Innovation, Spain), Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarollo Regional (FEDER; grant number BFU2016‐77961‐P), Direcció General de Recerca ‐ Generalitat de Catalunya (2017‐SGR‐00702), Unidad de Excelencia María de Maeztu (MINECO; MDM‐2014‐0370), and Vall d'Hebrón Institut de Recerca (predoctoral grants program 2014).-
dc.languageeng-
dc.publisherJohn Wiley & Sons-
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016-77961-P-
dc.relationinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/MDM-2014-0370-
dc.rightsclosedAccess-
dc.subjectRGS1-
dc.subjectinterferon-β-
dc.subjectMultiple sclerosis-
dc.subjectrare variants-
dc.subjectSingle nucleotide polymorphisms-
dc.subjecttargeted DNA sequencing-
dc.titleTargeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes-
dc.typeartículo-
dc.identifier.doi10.1002/humu.24016-
dc.relation.publisherversionhttp://dx.doi.org/10.1002/humu.24016-
dc.date.updated2020-07-16T09:40:22Z-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderAgencia Estatal de Investigación (España)-
dc.contributor.funderEuropean Commission-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderGeneralitat de Catalunya-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100002809es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004837es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003329es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100011033es_ES
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextNo Fulltext-
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