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Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression

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dc.creatorLu, Xiaomingspa
dc.creatorZoller, Erin E.spa
dc.creatorWeirauch, Matthew T.spa
dc.creatorWu, Zhiguospa
dc.creatorNamjou, Bahramspa
dc.creatorWilliams, Adrienne H.spa
dc.creatorZiegler, Julie T.spa
dc.creatorComeau, Mary E.spa
dc.creatorMarion, Miranda C.spa
dc.creatorGlenn, Stuart B.spa
dc.creatorAdler, Adamspa
dc.creatorShen, Nanspa
dc.creatorNath, Swapan K.spa
dc.creatorStevens, Anne M.spa
dc.creatorFreedman, Barry I.spa
dc.creatorTsao, Betty P.spa
dc.creatorJacob, Chaim O.spa
dc.creatorKamen, Diane L.spa
dc.creatorBrown, Elizabeth E.spa
dc.creatorGilkeson, Gary S.spa
dc.creatorAlarcón, Graciela S.spa
dc.creatorReveille, John D.spa
dc.creatorAnaya, Juan-Manuelspa
dc.creatorJames, Judith A.spa
dc.creatorSivils, Kathy L.spa
dc.creatorCriswell, Lindsey A.spa
dc.creatorVilá, Luis M.spa
dc.creatorAlarcón-Riquelme, Marta E.spa
dc.creatorPetri, Michellespa
dc.creatorScofield, R. Halspa
dc.creatorKimberly, Robert P.spa
dc.creatorRamsey-Goldman, Rosalindspa
dc.creatorBin Joo, Youngspa
dc.creatorChoi, Jeongimspa
dc.creatorBae, Sang-Cheolspa
dc.creatorBoackle, Susan A.spa
dc.creatorGraham, Deborah Cunninghamespa
dc.creatorVyse, Timothy J.spa
dc.creatorGuthridge, Joel M.spa
dc.creatorGaffney, Patrick M.spa
dc.creatorLangefeld, Carl D.spa
dc.creatorKelly, Jennifer A.spa
dc.creatorGreis, Kenneth D.spa
dc.creatorKaufman, Kenneth M.spa
dc.creatorHarley, John B.spa
dc.creatorKottyan, Leah C.spa
dc.date.accessioned2020-05-26T00:09:10Z
dc.date.available2020-05-26T00:09:10Z
dc.date.created2015spa
dc.description.abstractGenetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1. © 2015 by The American Society of Human Genetics. All rights reserved.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1016/j.ajhg.2015.03.002
dc.identifier.issn15376605
dc.identifier.issn00029297
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/24141
dc.language.isoengspa
dc.publisherCell Pressspa
dc.relation.citationEndPage739
dc.relation.citationIssueNo. 5
dc.relation.citationStartPage731
dc.relation.citationTitleAmerican Journal of Human Genetics
dc.relation.citationVolumeVol. 96
dc.relation.ispartofAmerican Journal of Human Genetics, ISSN:15376605, 00029297, Vol.96, No.5 (2015); pp. 731-739spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84929276935&doi=10.1016%2fj.ajhg.2015.03.002&partnerID=40&md5=0e6648d7e12d56710ee06807ce1fd6bfspa
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.keywordDnaspa
dc.subject.keywordsystemiceng
dc.subject.keywordMicrornaspa
dc.subject.keywordhumaneng
dc.subject.keywordStat1 proteinspa
dc.subject.keywordTranscription factorspa
dc.subject.keywordTranscription factor ets 1spa
dc.subject.keywordEts1 proteineng
dc.subject.keywordProtein bindingspa
dc.subject.keywordStat1 proteinspa
dc.subject.keywordTranscription factor ets 1spa
dc.subject.keywordAllelespa
dc.subject.keywordArticlespa
dc.subject.keywordAsianspa
dc.subject.keywordAutoimmunityspa
dc.subject.keywordB lymphocytespa
dc.subject.keywordBayesian learningspa
dc.subject.keywordChromatinspa
dc.subject.keywordChromatin immunoprecipitationspa
dc.subject.keywordGene locusspa
dc.subject.keywordGene mappingspa
dc.subject.keywordGenetic modelspa
dc.subject.keywordGenetic riskspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGenotypespa
dc.subject.keywordHan chinesespa
dc.subject.keywordHumanspa
dc.subject.keywordImmunoblottingspa
dc.subject.keywordMass spectrometryspa
dc.subject.keywordModelspa
dc.subject.keywordPriority journalspa
dc.subject.keywordProtein bindingspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAnimalspa
dc.subject.keywordAsian continental ancestry groupspa
dc.subject.keywordBayes theoremspa
dc.subject.keywordGenetic predispositionspa
dc.subject.keywordGeneticsspa
dc.subject.keywordHaplotypespa
dc.subject.keywordMetabolismspa
dc.subject.keywordMousespa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordMusspa
dc.subject.keywordAllelesspa
dc.subject.keywordAnimalsspa
dc.subject.keywordAsian continental ancestry groupspa
dc.subject.keywordBayes theoremspa
dc.subject.keywordGenetic predisposition to diseasespa
dc.subject.keywordGenotypespa
dc.subject.keywordHaplotypesspa
dc.subject.keywordHumansspa
dc.subject.keywordLupus erythematosuseng
dc.subject.keywordMicespa
dc.subject.keywordProtein bindingspa
dc.subject.keywordProto-oncogene protein c-ets-1spa
dc.subject.keywordStat1 transcription factorspa
dc.titleLupus risk variant increases pSTAT1 binding and decreases ETS1 expressionspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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