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Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

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dc.creatorDeng, Yunspa
dc.creatorZhao, Jianspa
dc.creatorSakurai, Daisukespa
dc.creatorSestak, Andrea Lspa
dc.creatorOsadchiy, Vadimspa
dc.creatorLangefeld, Carl Dspa
dc.creatorKaufman, Kenneth Mspa
dc.creatorKelly, Jennifer Aspa
dc.creatorJames, Judith Aspa
dc.creatorPetri, Michelle Aspa
dc.creatorBae, Sang-Cheolspa
dc.creatorAlarcón-Riquelme, Marta Espa
dc.creatorAlarcón, Graciela Sspa
dc.creatorAnaya, Juan-Manuelspa
dc.creatorCriswell, Lindsey Aspa
dc.creatorFreedman, Barry Ispa
dc.creatorKamen, Diane Lspa
dc.creatorGilkeson, Gary Sspa
dc.creatorJacob, Chaim Ospa
dc.creatorMerrill, Joan Tspa
dc.creatorGaffney, Patrick Mspa
dc.creatorSivils, Kathy Moserspa
dc.creatorNiewold, Timothy Bspa
dc.creatorRamsey-Goldman, Rosalindspa
dc.creatorReveille, John Dspa
dc.creatorScofield, R Halspa
dc.creatorStevens, Anne Mspa
dc.creatorBoackle, Susan Aspa
dc.creatorVilá, Luis Mspa
dc.creatorSohn, I I Woongspa
dc.creatorLee, Seungspa
dc.creatorChang, Deh-Mingspa
dc.creatorSong, Yeong Wookspa
dc.creatorVyse, Timothy Jspa
dc.creatorHarley, John Bspa
dc.creatorBrown, Elizabeth Espa
dc.creatorEdberg, Jeffrey Cspa
dc.creatorKimberly, Robert Pspa
dc.creatorCantor, Rita Mspa
dc.creatorHahn, Bevra Hspa
dc.creatorGrossman, Jennifer Mspa
dc.creatorTsao, Betty Pspa
dc.date.accessioned2020-05-25T23:56:33Z
dc.date.available2020-05-25T23:56:33Z
dc.date.created2016spa
dc.description.abstractObjectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150a €...kb flanking regions containing NMNAT2 and SMG7 in a 15a €...292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 a '8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 a '3 and 6.8×10 a '8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=a '0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 a '5 and 2.0×10 a '4, respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis. © 2016 Published by the BMJ Publishing Group Limited.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1136/annrheumdis-2015-208441
dc.identifier.issn00034967
dc.identifier.issn14682060
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/22456
dc.language.isoengspa
dc.publisherBMJ Publishing Groupspa
dc.relation.citationEndPage2013
dc.relation.citationIssueNo. 11
dc.relation.citationStartPage2007
dc.relation.citationTitleAnnals of the Rheumatic Diseases
dc.relation.citationVolumeVol. 75
dc.relation.ispartofAnnals of the Rheumatic Diseases, ISSN:00034967, 14682060, Vol.75, No.11 (2016); pp. 2007-2013spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84956688448&doi=10.1136%2fannrheumdis-2015-208441&partnerID=40&md5=99327f1cad95fc1b593eb80bc79030c1spa
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.keywordAntinuclear antibodyspa
dc.subject.keywordsystemiceng
dc.subject.keywordImmunoglobulin gspa
dc.subject.keywordantinucleareng
dc.subject.keywordhumaneng
dc.subject.keywordhumaneng
dc.subject.keywordmessengereng
dc.subject.keywordmononucleareng
dc.subject.keywordRibonucleoprotein antibodyspa
dc.subject.keywordSm antibodyspa
dc.subject.keywordSmall interfering rnaspa
dc.subject.keywordAntinuclear antibodyspa
dc.subject.keywordCarrier proteinspa
dc.subject.keywordMessenger rnaspa
dc.subject.keywordNicotinamide nucleotide adenylyltransferasespa
dc.subject.keywordNmnat2 proteineng
dc.subject.keywordSmg7 proteineng
dc.subject.keywordAllelespa
dc.subject.keywordAntibody productionspa
dc.subject.keywordAntibody titerspa
dc.subject.keywordArticlespa
dc.subject.keywordCase control studyspa
dc.subject.keywordCell culturespa
dc.subject.keywordControlled studyspa
dc.subject.keywordCorrelational studyspa
dc.subject.keywordEmbryospa
dc.subject.keywordEthnic differencespa
dc.subject.keywordGenespa
dc.subject.keywordGene expressionspa
dc.subject.keywordGene functionspa
dc.subject.keywordGene linkage disequilibriumspa
dc.subject.keywordGene silencingspa
dc.subject.keywordGenetic associationspa
dc.subject.keywordGenetic transcriptionspa
dc.subject.keywordGenetic variabilityspa
dc.subject.keywordGenotypespa
dc.subject.keywordHumanspa
dc.subject.keywordHuman cellspa
dc.subject.keywordLuciferase assayspa
dc.subject.keywordMajor clinical studyspa
dc.subject.keywordMulticenter study (topic)spa
dc.subject.keywordNmnat2 genespa
dc.subject.keywordPeripheral blood mononuclear cellspa
dc.subject.keywordPriority journalspa
dc.subject.keywordPromoter regionspa
dc.subject.keywordQuantitative trait locusspa
dc.subject.keywordRaji cell linespa
dc.subject.keywordReal time polymerase chain reactionspa
dc.subject.keywordRegulatory mechanismspa
dc.subject.keywordRiskspa
dc.subject.keywordSingle nucleotide polymorphismspa
dc.subject.keywordSmg7 genespa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAmerican indianspa
dc.subject.keywordCaucasianspa
dc.subject.keywordFemalespa
dc.subject.keywordGenetic predispositionspa
dc.subject.keywordGeneticsspa
dc.subject.keywordGenome-wide association studyspa
dc.subject.keywordGenotyping techniquespa
dc.subject.keywordHek293 cell linespa
dc.subject.keywordHispanicspa
dc.subject.keywordImmunologyspa
dc.subject.keywordMalespa
dc.subject.keywordMetabolismspa
dc.subject.keywordMononuclear cellspa
dc.subject.keywordPedigreespa
dc.subject.keywordRisk factorspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.subject.keywordAllelesspa
dc.subject.keywordAmerican native continental ancestry groupspa
dc.subject.keywordAntibodieseng
dc.subject.keywordCarrier proteinsspa
dc.subject.keywordEuropean continental ancestry groupspa
dc.subject.keywordFemalespa
dc.subject.keywordGenetic predisposition to diseasespa
dc.subject.keywordGenome-wide association studyspa
dc.subject.keywordGenotyping techniquesspa
dc.subject.keywordHek293 cellsspa
dc.subject.keywordHispanic americansspa
dc.subject.keywordHumansspa
dc.subject.keywordLeukocyteseng
dc.subject.keywordLinkage disequilibriumspa
dc.subject.keywordLupus erythematosuseng
dc.subject.keywordMalespa
dc.subject.keywordNicotinamide-nucleotide adenylyltransferasespa
dc.subject.keywordPedigreespa
dc.subject.keywordReal-time polymerase chain reactionspa
dc.subject.keywordRisk factorsspa
dc.subject.keywordRnaeng
dc.subject.keywordAutoantibodiesspa
dc.subject.keywordGene polymorphismspa
dc.subject.keywordSystemic lupus erythematosusspa
dc.titleDecreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody productionspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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