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Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA

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dc.creatorZhao, Jianspa
dc.creatorGiles, Brendan Mspa
dc.creatorTaylor, Rhonda Lspa
dc.creatorYette, Gabriel Aspa
dc.creatorLough, Kara Mspa
dc.creatorNg, Han Lengspa
dc.creatorAbraham, Lawrence Jspa
dc.creatorWu, Huispa
dc.creatorKelly, Jennifer Aspa
dc.creatorGlenn, Stuart Bspa
dc.creatorAdler, Adam Jspa
dc.creatorWilliams, Adrienne Hspa
dc.creatorComeau, Mary Espa
dc.creatorZiegler, Julie Tspa
dc.creatorMarion, Mirandaspa
dc.creatorAlarcón-Riquelme, Marta Espa
dc.creatorAlarcón, Graciela Sspa
dc.creatorAnaya, Juan-Manuelspa
dc.creatorBae, Sang-Cheolspa
dc.creatorKim, Damspa
dc.creatorLee, Hye-Soonspa
dc.creatorCriswell, Lindsey Aspa
dc.creatorFreedman, Barry Ispa
dc.creatorGilkeson, Gary Sspa
dc.creatorGuthridge, Joel Mspa
dc.creatorJacob, Chaim Ospa
dc.creatorJames, Judith Aspa
dc.creatorKamen, Diane Lspa
dc.creatorMerrill, Joan Tspa
dc.creatorSivils, Kathy Moserspa
dc.creatorNiewold, Timothy Bspa
dc.creatorPetri, Michelle Aspa
dc.creatorRamsey-Goldman, Rosalindspa
dc.creatorReveille, John Dspa
dc.creatorScofield, R Halspa
dc.creatorStevens, Anne Mspa
dc.creatorVilá, Luis Mspa
dc.creatorVyse, Timothy Jspa
dc.creatorKaufman, Kenneth Mspa
dc.creatorHarley, John Bspa
dc.creatorLangefeld, Carl Dspa
dc.creatorGaffney, Patrick Mspa
dc.creatorBrown, Elizabeth Espa
dc.creatorEdberg, Jeffrey Cspa
dc.creatorKimberly, Robert Pspa
dc.creatorUlgiati, Danielaspa
dc.creatorTsao, Betty Pspa
dc.creatorBoackle, Susan Aspa
dc.date.accessioned2020-05-25T23:56:30Z
dc.date.available2020-05-25T23:56:30Z
dc.date.created2016spa
dc.description.abstractObjectives Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. Methods Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. Results The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10-4, OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10-7, OR 0.71; case-only pmeta=1.9×10-4, OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. Conclusions These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1136/annrheumdis-2014-205584
dc.identifier.issn00034967
dc.identifier.issn14682060
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22444
dc.language.isoengspa
dc.publisherBMJ Publishing Groupspa
dc.relation.citationEndPage252
dc.relation.citationIssueNo. 1
dc.relation.citationStartPage242
dc.relation.citationTitleAnnals of the Rheumatic Diseases
dc.relation.citationVolumeVol. 75
dc.relation.ispartofAnnals of the Rheumatic Diseases, ISSN:00034967, 14682060, Vol.75, No.1 (2016); pp. 242-252spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84954322451&doi=10.1136%2fannrheumdis-2014-205584&partnerID=40&md5=e3852eae3ac6476dd9b1ee51101803f8spa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordComplement component C3b receptorspa
dc.subject.keywordSystemiceng
dc.subject.keywordComplement receptorspa
dc.subject.keywordAntinucleareng
dc.subject.keywordSingle Nucleotideeng
dc.subject.keywordComplement receptor 2spa
dc.subject.keywordDouble stranded DNA antibodyspa
dc.subject.keywordMessenger RNAspa
dc.subject.keywordTranscription factor CTCFspa
dc.subject.keywordUnclassified drugspa
dc.subject.keywordAntinuclear antibodyspa
dc.subject.keywordComplement component C3b receptorspa
dc.subject.keywordComplement component C3d receptorspa
dc.subject.keywordCR1 protein, humanspa
dc.subject.keywordDNAspa
dc.subject.keywordTranscription factorspa
dc.subject.keywordAllelespa
dc.subject.keywordArticlespa
dc.subject.keywordB lymphocytespa
dc.subject.keywordCase control studyspa
dc.subject.keywordChromatin immunoprecipitationspa
dc.subject.keywordControlled studyspa
dc.subject.keywordDNA protein complexspa
dc.subject.keywordFlow cytometryspa
dc.subject.keywordGel mobility shift assayspa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGenotypespa
dc.subject.keywordHumanspa
dc.subject.keywordIntronspa
dc.subject.keywordMajor clinical studyspa
dc.subject.keywordPathogenesisspa
dc.subject.keywordPriority journalspa
dc.subject.keywordReal time polymerase chain reactionspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAdolescentspa
dc.subject.keywordAdultspa
dc.subject.keywordBiosynthesisspa
dc.subject.keywordBloodspa
dc.subject.keywordGenetic predispositionspa
dc.subject.keywordGenetic variationspa
dc.subject.keywordGeneticsspa
dc.subject.keywordHaplotypespa
dc.subject.keywordImmunologyspa
dc.subject.keywordMetabolismspa
dc.subject.keywordMiddle agedspa
dc.subject.keywordPhenotypespa
dc.subject.keywordProceduresspa
dc.subject.keywordRisk assessmentspa
dc.subject.keywordSingle nucleotide polymorphismspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordYoung adultspa
dc.subject.keywordAdolescentspa
dc.subject.keywordAdultspa
dc.subject.keywordAntibodieseng
dc.subject.keywordB-Lymphocyte Subsetsspa
dc.subject.keywordCase-Control Studiesspa
dc.subject.keywordDNAspa
dc.subject.keywordGenetic Predisposition to Diseasespa
dc.subject.keywordGenetic Variationspa
dc.subject.keywordGenotypespa
dc.subject.keywordHaplotypesspa
dc.subject.keywordHumansspa
dc.subject.keywordLupus Erythematosuseng
dc.subject.keywordMiddle Agedspa
dc.subject.keywordPhenotypespa
dc.subject.keywordPolymorphismeng
dc.subject.keywordReceptors, Complement 3dspa
dc.subject.keywordRisk Assessmentspa
dc.subject.keywordTranscription Factorsspa
dc.subject.keywordYoung Adultspa
dc.titlePreferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNAspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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