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A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus

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dc.creatorPatel, Zubin Hspa
dc.creatorLu, Xiaomingspa
dc.creatorMiller, Danielspa
dc.creatorForney, Carmy Rspa
dc.creatorLee, Joshuaspa
dc.creatorLynch, Arthurspa
dc.creatorSchroeder, Connorspa
dc.creatorParks, Loisspa
dc.creatorMagnusen, Albert Fspa
dc.creatorChen, Xiaotingspa
dc.creatorPujato, Mariospa
dc.creatorMaddox, Averyspa
dc.creatorZoller, Erin Espa
dc.creatorNamjou, Bahramspa
dc.creatorBrunner, Hermine Ispa
dc.creatorHenrickson, Michaelspa
dc.creatorHuggins, Jennifer Lspa
dc.creatorWilliams, Adrienne Hspa
dc.creatorZiegler, Julie Tspa
dc.creatorComeau, Mary Espa
dc.creatorMarion, Miranda Cspa
dc.creatorGlenn, Stuart Bspa
dc.creatorAdler, Adamspa
dc.creatorShen, Nanspa
dc.creatorNath, Swapan Kspa
dc.creatorStevens, Anne Mspa
dc.creatorFreedman, Barry Ispa
dc.creatorPons-Estel, Bernardo Aspa
dc.creatorTsao, Betty Pspa
dc.creatorJacob, Chaim Ospa
dc.creatorKamen, Diane Lspa
dc.creatorBrown, Elizabeth Espa
dc.creatorGilkeson, Gary Sspa
dc.creatorAlarcón, Graciela Sspa
dc.creatorMartin, Javierspa
dc.creatorReveille, John Dspa
dc.creatorAnaya, Juan-Manuelspa
dc.creatorJames, Judith Aspa
dc.creatorSivils, Kathy Lspa
dc.creatorCriswell, Lindsey Aspa
dc.creatorVilá, Luis Mspa
dc.creatorPetri, Michellespa
dc.creatorScofield, R Halspa
dc.creatorKimberly, Robert Pspa
dc.creatorEdberg, Jeffrey Cspa
dc.creatorRamsey-Goldman, Rosalindspa
dc.creatorBang, So-Youngspa
dc.creatorLee, Hye-Soonspa
dc.creatorBae, Sang-Cheolspa
dc.creatorBoackle, Susan Aspa
dc.creatorGraham, Deborah Cunninghamespa
dc.creatorVyse, Timothy Jspa
dc.creatorMerrill, Joan Tspa
dc.creatorNiewold, Timothy Bspa
dc.creatorAinsworth, Hannah Cspa
dc.creatorSilverman, Earl Dspa
dc.creatorWeisman, Michael Hspa
dc.creatorWallace, Daniel Jspa
dc.creatorRaj, Prithvispa
dc.creatorGuthridge, Joel Mspa
dc.creatorGaffney, Patrick Mspa
dc.creatorKelly, Jennifer Aspa
dc.creatorAlarcón-Riquelme, Marta Espa
dc.creatorLangefeld, Carl Dspa
dc.creatorWakeland, Edward Kspa
dc.creatorKaufman, Kenneth Mspa
dc.creatorWeirauch, Matthew Tspa
dc.creatorHarley, John Bspa
dc.creatorKottyan, Leah Cspa
dc.date.accessioned2020-05-26T00:10:23Z
dc.date.available2020-05-26T00:10:23Z
dc.date.created2018spa
dc.description.abstractSystemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341.We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/hmg/ddy140
dc.identifier.issn14602083
dc.identifier.issn09646906
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/24225
dc.language.isoengspa
dc.publisherOxford University Pressspa
dc.relation.citationEndPage2404
dc.relation.citationIssueNo. 13
dc.relation.citationStartPage2392
dc.relation.citationTitleHuman Molecular Genetics
dc.relation.citationVolumeVol. 27
dc.relation.ispartofHuman Molecular Genetics, ISSN:14602083, 09646906, Vol.27, No.13 (2018); pp. 2392-2404spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85050807803&doi=10.1093%2fhmg%2fddy140&partnerID=40&md5=867b9ae93ec14f6623918cceaf4f8655spa
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.keywordHigh mobility group A proteinspa
dc.subject.keywordSystemiceng
dc.subject.keywordHMGA1 proteinspa
dc.subject.keywordGeneticeng
dc.subject.keywordhumaneng
dc.subject.keywordhumaneng
dc.subject.keywordSTAT1 proteinspa
dc.subject.keywordSTAT4 proteinspa
dc.subject.keywordUnclassified drugspa
dc.subject.keywordSTAT1 proteinspa
dc.subject.keywordSTAT1 proteineng
dc.subject.keywordSTAT4 proteinspa
dc.subject.keywordSTAT4 proteineng
dc.subject.keywordAllelespa
dc.subject.keywordArticlespa
dc.subject.keywordB-lymphocyte cell linespa
dc.subject.keywordControlled studyspa
dc.subject.keywordDNA bindingspa
dc.subject.keywordExpression quantitative trait locusspa
dc.subject.keywordFunctional diseasespa
dc.subject.keywordGene locusspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordHumanspa
dc.subject.keywordIntronspa
dc.subject.keywordLupus vulgarisspa
dc.subject.keywordPriority journalspa
dc.subject.keywordProtein domainspa
dc.subject.keywordProtein expressionspa
dc.subject.keywordAllelespa
dc.subject.keywordClinical trialspa
dc.subject.keywordFemalespa
dc.subject.keywordGenetic polymorphismspa
dc.subject.keywordGeneticsspa
dc.subject.keywordMalespa
dc.subject.keywordMulticenter studyspa
dc.subject.keywordQuantitative trait locusspa
dc.subject.keywordRisk factorspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAllelesspa
dc.subject.keywordFemalespa
dc.subject.keywordHumansspa
dc.subject.keywordLupus Erythematosuseng
dc.subject.keywordMalespa
dc.subject.keywordPolymorphismeng
dc.subject.keywordQuantitative Trait Locispa
dc.subject.keywordRisk Factorsspa
dc.subject.keywordSTAT1 Transcription Factorspa
dc.subject.keywordSTAT4 Transcription Factorspa
dc.titleA plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locusspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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