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Combined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAM

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dc.creatorMaiti, Amit K.spa
dc.creatorKim-Howard, Xanaspa
dc.creatorMotghare, Prasenjeetspa
dc.creatorPradhan, Vandanaspa
dc.creatorChua, Kek Hengspa
dc.creatorSun, Celispa
dc.creatorArango-Guerrero, María Teresaspa
dc.creatorGhosh, Kanjakshaspa
dc.creatorNiewold, Timothy B.spa
dc.creatorHarley, John B.spa
dc.creatorAnaya, Juan-Manuelspa
dc.creatorLooger, Loren L.spa
dc.creatorNath, Swapan K.spa
dc.date.accessioned2020-05-26T00:10:18Z
dc.date.available2020-05-26T00:10:18Z
dc.date.created2014spa
dc.description.abstractIntegrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' and lt; 'AG' and lt; 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/hmg/ddu106
dc.identifier.issn14602083
dc.identifier.issn09646906
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/24222
dc.language.isoengspa
dc.publisherOxford University Pressspa
dc.relation.citationEndPage4176
dc.relation.citationIssueNo. 15
dc.relation.citationStartPage4161
dc.relation.citationTitleHuman Molecular Genetics
dc.relation.citationVolumeVol. 23
dc.relation.ispartofHuman Molecular Genetics, ISSN:14602083, 09646906, Vol.23, No.15 (2014); pp. 4161-4176spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84904003200&doi=10.1093%2fhmg%2fddu106&partnerID=40&md5=9286ba2c48041a3d18c6f1fd25414210spa
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.keywordAlpha integrinspa
dc.subject.keywordhumaneng
dc.subject.keywordmessengereng
dc.subject.keywordhumaneng
dc.subject.keywordhumaneng
dc.subject.keywordgeneticeng
dc.subject.keywordgeneticeng
dc.subject.keywordcd11beng
dc.subject.keywordnucleareng
dc.subject.keywordsystemiceng
dc.subject.keywordCd11b antigenspa
dc.subject.keywordEarly b cell factor 1spa
dc.subject.keywordFibrinogenspa
dc.subject.keywordIntegrin alpha mspa
dc.subject.keywordKu antigenspa
dc.subject.keywordKu70/80spa
dc.subject.keywordNfkb1 proteinspa
dc.subject.keywordNucleic acidspa
dc.subject.keywordProteinspa
dc.subject.keywordRnaspa
dc.subject.keywordTranscription factorspa
dc.subject.keywordUnclassified drugspa
dc.subject.keywordVitronectinspa
dc.subject.keywordCd11b antigenspa
dc.subject.keywordCell nucleus antigenspa
dc.subject.keywordChromatinspa
dc.subject.keywordDna binding proteinspa
dc.subject.keywordEbf1 proteineng
dc.subject.keywordFibrinogenspa
dc.subject.keywordImmunoglobulin enhancer binding proteinspa
dc.subject.keywordItgam proteineng
dc.subject.keywordKu antigenspa
dc.subject.keywordMessenger rnaspa
dc.subject.keywordNfkb1 proteineng
dc.subject.keywordProtein bindingspa
dc.subject.keywordTransactivator proteinspa
dc.subject.keywordVitronectinspa
dc.subject.keywordAllelespa
dc.subject.keywordAncestry groupspa
dc.subject.keywordArticlespa
dc.subject.keywordChromatinspa
dc.subject.keywordGene functionspa
dc.subject.keywordGene locusspa
dc.subject.keywordGenetic analysisspa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic predispositionspa
dc.subject.keywordGenetic riskspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGenotypespa
dc.subject.keywordHeterozygotespa
dc.subject.keywordHumanspa
dc.subject.keywordIn vitro studyspa
dc.subject.keywordIn vivo studyspa
dc.subject.keywordLigand bindingspa
dc.subject.keywordMeta analysisspa
dc.subject.keywordMissense mutationspa
dc.subject.keywordMonocytespa
dc.subject.keywordPriority journalspa
dc.subject.keywordProtein bindingspa
dc.subject.keywordProtein expressionspa
dc.subject.keywordRna degradationspa
dc.subject.keywordSingle nucleotide polymorphismspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordEthnologyspa
dc.subject.keywordFemalespa
dc.subject.keywordGene expression regulationspa
dc.subject.keywordGene frequencyspa
dc.subject.keywordGenetic polymorphismspa
dc.subject.keywordGenetic transcriptionspa
dc.subject.keywordGeneticsspa
dc.subject.keywordMalespa
dc.subject.keywordMetabolismspa
dc.subject.keywordPathologyspa
dc.subject.keywordRiskspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAllelesspa
dc.subject.keywordAntigenseng
dc.subject.keywordAntigenseng
dc.subject.keywordChromatinspa
dc.subject.keywordContinental population groupsspa
dc.subject.keywordDna-binding proteinsspa
dc.subject.keywordFemalespa
dc.subject.keywordFibrinogenspa
dc.subject.keywordGene expression regulationspa
dc.subject.keywordGene frequencyspa
dc.subject.keywordGenetic predisposition to diseasespa
dc.subject.keywordHumansspa
dc.subject.keywordLupus erythematosuseng
dc.subject.keywordMalespa
dc.subject.keywordMonocytesspa
dc.subject.keywordNf-kappa b p50 subunitspa
dc.subject.keywordOdds ratiospa
dc.subject.keywordPolymorphismeng
dc.subject.keywordProtein bindingspa
dc.subject.keywordRiskspa
dc.subject.keywordRnaeng
dc.subject.keywordTrans-activatorsspa
dc.subject.keywordTranscriptioneng
dc.subject.keywordVitronectinspa
dc.titleCombined protein-and nucleic acid-level effects of rs1143679 (R77H), a lupus-predisposing variant within ITGAMspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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