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Preferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expression

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dc.creatorSakurai, Daisuke
dc.creatorZhao, Jian
dc.creatorDeng, Yun
dc.creatorKelly, Jennifer A.
dc.creatorBrown, Elizabeth E.
dc.creatorHarley, John B.
dc.creatorBae, Sang-Cheol
dc.creatorAlarcón-Riquelme, Marta E.
dc.creatorEdberg, Jeffrey C.
dc.creatorKimberly, Robert P.
dc.creatorRamsey-Goldman, Rosalind
dc.creatorPetri, Michelle A.
dc.creatorReveille, John D.
dc.creatorVilá, Luis M.
dc.creatorAlarcón, Graciela S.
dc.creatorKaufman, Kenneth M.
dc.creatorVyse, Timothy J.
dc.creatorJacob, Chaim O.
dc.creatorGaffney, Patrick M.
dc.creatorMoser Sivils, Kathy
dc.creatorJames, Judith A.
dc.creatorKamen, Diane L.
dc.creatorGilkeson, Gary S.
dc.creatorNiewold, Timothy B.
dc.creatorMerrill, Joan T.
dc.creatorScofield, Robert H.
dc.creatorCriswell, Lindsey A.
dc.creatorStevens, Anne M.
dc.creatorBoackle, Susan
dc.creatorKim, Jae-Hoon
dc.creatorChoi, Jiyoung
dc.creatorPons-Estel, Bernardo A.
dc.creatorFreedman, Barry I.
dc.creatorAnaya, Juan-Manuel
dc.creatorMartin, Javier
dc.creatorYu, Chack-Yung
dc.creatorChang, Deh-Ming
dc.creatorSong, Yeong Wook
dc.creatorLangefeld, Carl D.
dc.creatorChen, Weiling
dc.creatorGrossman, Jennifer M.
dc.creatorCantor, Rita M.
dc.creatorHahn, Bevra H.
dc.creatorTsao, Betty P.
dc.creator.googleEdberg, Jeffrey C.
dc.creator.googleKimberly, Robert P.
dc.creator.googleRamsey-Goldman, Rosalind
dc.creator.googlePetri, Michelle A.
dc.creator.googleReveille, John D.
dc.creator.googleVilá, Luis M.
dc.creator.googleAlarcón, Graciela S.
dc.creator.googleKaufman, Kenneth M.
dc.creator.googleVyse, Timothy J.
dc.creator.googleJacob, Chaim O.
dc.creator.googleGaffney, Patrick M.
dc.creator.googleSivils, Kathy Moser
dc.creator.googleJames, Judith A.
dc.creator.googleKamen, Diane L.
dc.creator.googleGilkeson, Gary S.
dc.creator.googleNiewold, Timothy B.
dc.creator.googleMerrill, Joan T.
dc.creator.googleScofield, R. Hal
dc.creator.googleCriswell, Lindsey A.
dc.creator.googleStevens, Anne M.
dc.creator.googleBoackle, Susan A.
dc.creator.googleKim, Jae-Hoon
dc.creator.googleChoi, Jiyoung
dc.creator.googlePons-Estel, Bernardo A.
dc.creator.googleFreedman, Barry I.
dc.creator.googleAnaya, Juan-Manuel
dc.creator.googleMartin, Javier
dc.creator.googleYu, C. Yung
dc.creator.googleChang, Deh-Ming
dc.creator.googleSong, Yeong Wook
dc.creator.googleLangefeld, Carl D.
dc.creator.googleChen, Weilling
dc.creator.googleGrossman, Jennifer M.
dc.creator.googleCantor, Rita M.
dc.creator.googleHahn, Bevra H.
dc.creator.googleTsao, Betty P.
dc.creator.googleSakurai, Daisuke
dc.creator.googleZhao, Jian
dc.creator.googleDeng, Yun
dc.creator.googleKelly, Jennifer A.
dc.creator.googleBrown, Elizabeth E.
dc.creator.googleHarley, John B.
dc.creator.googleBae, Sang-Cheol
dc.creator.googleAlarcón-Riquelme, Martha E.
dc.date.accessioned2014-08-13T15:54:16Z
dc.date.available2014-08-13T15:54:16Z
dc.date.created2013
dc.date.issued2013-10-10
dc.description.abstractImmunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.eng
dc.format.mediumRecurso electrónicospa
dc.format.mimetypeapplication/pdf
dc.format.tipoDocumentospa
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1003870
dc.identifier.issn1553-7390
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/8828
dc.language.isoeng
dc.publisherUniversidad del Rosariospa
dc.relation.citationIssueNo. 10
dc.relation.citationTitlePLoS Genetics
dc.relation.citationVolumeVol. 9
dc.relation.ispartofPLoS Genetics ISSN: 15537390 V. 9 N. 10, 2013spa
dc.relation.urihttp://www.plosgenetics.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1003870&representation=PDF
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto completo)spa
dc.rights.licenciaEL AUTOR, manifiesta que la obra objeto de la presente autorización es original y la realizó sin violar o usurpar derechos de autor de terceros, por lo tanto la obra es de exclusiva autoría y tiene la titularidad sobre la misma.spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.ddcEnfermedades
dc.subject.decsLupus eritematoso sistémicospa
dc.subject.decsEnfermedades autoinmunesspa
dc.subject.decsInmunologíaspa
dc.subject.keywordInterleukin 10eng
dc.subject.keywordTGranscription factor Elk 1eng
dc.subject.keywordBinding affinityeng
dc.subject.keywordControlled studyeng
dc.subject.keywordDisease activityeng
dc.subject.keywordDisease predispositioneng
dc.subject.keywordDown regulationeng
dc.subject.keywordGeneeng
dc.subject.keywordGene clustereng
dc.titlePreferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expressionspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaArtículospa
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