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MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus

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dc.audienceComunidad Rosaristaspa
dc.creatorDeng, Yun
dc.creatorZhao, Jian
dc.creatorSakurai, Daisuke
dc.creatorKaufman, Kenneth M.
dc.creatorEdberg, Jeffrey C.
dc.creatorKimberly, Robert P.
dc.creatorKamen, Diane L.
dc.creatorGilkeson, Gary S.
dc.creatorJacob, Chaim O.
dc.creatorScofield, Robert H.
dc.creatorLangefeld, Carl D.
dc.creatorKelly, Jennifer A.
dc.creatorRamsey-Goldman, Rosalind
dc.creatorPetri, Michelle A.
dc.creatorReveille, John D.
dc.creatorVilá, Luis M.
dc.creatorAlarcón, Graciela S.
dc.creatorVyse, Timothy J.
dc.creatorPons-Estel, Bernardo A.
dc.creatorFreedman, Barry I.
dc.creatorGaffney, Patrick M.
dc.creatorMoser Sivils, Kathy
dc.creatorJames, Judith A.
dc.creatorGregersen, Peter K.
dc.creatorAnaya, Juan-Manuel
dc.creatorNiewold, Timothy B.
dc.creatorMerrill, Joan T.
dc.creatorCriswell, Lindsey A.
dc.creatorStevens, Anne M.
dc.creatorBoackle, Susan
dc.creatorCantor, Rita M.
dc.creatorChen, Weiling
dc.creatorGrossman, Jenniffer M.
dc.creatorHahn, Bevra H.
dc.creatorHarley, John B.
dc.creatorAlarcón-Riquelme, Marta E.
dc.creatorBrown, Elizabeth E.
dc.creatorTsao, Betty P.
dc.creator.googleDeng, Yun
dc.creator.googleZhao, Jian
dc.creator.googleSakurai, Daisuke
dc.creator.googleKaufman, Kenneth M.
dc.creator.googleEdberg, Jeffrey C.
dc.creator.googleKimberly, Robert P.
dc.creator.googleKamen, Diane L.
dc.creator.googleGilkeson, Gary S.
dc.creator.googleJacob, Chaim O.
dc.creator.googleScofield, R. Hal
dc.creator.googleLangefeld, Carl D.
dc.creator.googleKelly, Jennifer A.
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.googleVyse, Timothy J.
dc.creator.googlePons-Estel, Bernardo A.
dc.creator.googleFreedman, Barry I.
dc.creator.googleGaffney, Patrick M.
dc.creator.googleMoser Sivils, Kathy
dc.creator.googleJames, Judith A.
dc.creator.googleGregersen, Peter K.
dc.creator.googleAnaya, Juan-Manuel
dc.creator.googleNiewold, Timothy B.
dc.creator.googleMerril, Joan T.
dc.creator.googleCriswell, Lindsey A.
dc.creator.googleStevens, Anne M.
dc.creator.googleBoackle, Susan A.
dc.creator.googleCantor, Rita M.
dc.creator.googleChen, Weiling
dc.creator.googleGrossman, Jeniffer M.
dc.creator.googleHahn, Bevra H.
dc.creator.googleHarley, John B.
dc.creator.googleAlarcón-Riquelme, Marta E.
dc.creator.googleBrown, Elizabeth E.
dc.creator.googleTsao, Betty P.
dc.date.accessioned2014-08-12T16:51:04Z
dc.date.available2014-08-12T16:51:04Z
dc.date.created2013-02-28
dc.date.issued2013
dc.description.abstractWe previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10−10, odds ratio (OR) (95%CI) = 1.27 (1.17–1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10−11, OR = 1.24 [1.18–1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10−19, OR = 1.25 [1.20–1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.eng
dc.format.mediumRecurso electrónicospa
dc.format.mimetypeapplication/pdf
dc.format.tipoDocumentospa
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1003336
dc.identifier.issn1553-7404
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/8810
dc.language.isoeng
dc.publisherUniversidad del Rosariospa
dc.relation.citationIssueNo. 2
dc.relation.citationTitlePLOS GENETICS
dc.relation.citationVolumeVol. 9
dc.relation.ispartofPLOS GENETICS ISSN: 1553-7404 V. 9 N. 2 Feb, 2013spa
dc.relation.urihttp://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003336
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.decsGenoma humanospa
dc.subject.decsEnfermedades autoinmunesspa
dc.subject.decsInmunologíaspa
dc.subject.decsLupus eritematoso sistémicospa
dc.subject.keywordGenome-wide associationeng
dc.subject.keywordImmune-responseseng
dc.subject.keywordTLR7eng
dc.subject.keywordSusceptibilityeng
dc.subject.keywordPolymorphismseng
dc.subject.keywordAutoimmunityeng
dc.subject.keywordPopulationeng
dc.subject.keywordITGAMeng
dc.subject.keywordWomeneng
dc.subject.keywordLOCIeng
dc.titleMicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosusspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/acceptedVersion
dc.type.spaArtículospa
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