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Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

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dc.creatorLi, He
dc.creatorReksten, Tove Ragna
dc.creatorIce, John A.
dc.creatorKelly, Jennifer A.
dc.creatorAdrianto, Indra
dc.creatorRasmussen, Astrid
dc.creatorWang, Shaofeng
dc.creatorHe, Bo
dc.creatorGrundahl, Kiely M.
dc.creatorGlenn, Stuart B.
dc.creatorMiceli-Richard, Corinne
dc.creatorBowman, Simon
dc.creatorLester, Sue
dc.creatorEriksson, Per
dc.creatorEloranta, Maija-Leena
dc.creatorBrun, Johan G.
dc.creatorGøransson, Lasse G.
dc.creatorHarboe, Erna
dc.creatorGuthridge, Joel M.
dc.creatorKaufman, Kenneth M.
dc.creatorKvarnström, Marika
dc.creatorCunninghame Graham, Deborah S.
dc.creatorPatel, Ketan
dc.creatorAdler, Adam J.
dc.creatorFarris, A. Darise
dc.creatorBrennan, Michael T.
dc.creatorChodosh, James
dc.creatorGopalakrishnan, Rajaram
dc.creatorWeisman, Michael H.
dc.creatorVenuturupalli, Swamy
dc.creatorWallace, Daniel J.
dc.creatorHefner, Kimberly S.
dc.creatorHouston, Glen D.
dc.creatorHuang, Andrew J. W.
dc.creatorHughes, Pamela J.
dc.creatorLewis, David M.
dc.creatorRadfar, Lida
dc.creatorVista, Evan S.
dc.creatorContessa E., Edgar
dc.creatorRohrer, Michael D.
dc.creatorStone, Donald U.
dc.creatorVyse, Timothy J.
dc.creatorHarley, John B.
dc.creatorGaffney, Patrick M.
dc.creatorJames, Judith A.
dc.creatorTurner, Sean
dc.creatorAlevizos, Ilias
dc.creatorAnaya, Juan-Manuel
dc.creatorRhodus, Nelson L.
dc.creatorSegal, Barbara M.
dc.creatorMontgomery, Courtney G.
dc.creatorScofield, R. Hal
dc.creatorKovats, Susan
dc.creatorMariette, Xavier
dc.creatorRönnblom, Lars
dc.creatorWitte, Torsten
dc.creatorRischmueller, Maureen
dc.creatorWahren-Herlenius, Marie
dc.creatorOmdal, Roald
dc.creatorJonsson, Roland
dc.creatorNg, Wan-Fai
dc.creatorNordmark, Gunnel
dc.creatorLessard, Christopher J.
dc.creatorSivils, Kathy L.
dc.creator.googleLi, Hespa
dc.creator.googleReksten, Tove Ragnaspa
dc.creator.googleIce, John A.spa
dc.creator.googleKelly, Jennifer A.spa
dc.creator.googleAdrianto, Indraspa
dc.creator.googleRasmussen, Astridspa
dc.creator.googleWang, Shaofengspa
dc.creator.googleHe, Bospa
dc.creator.googleGrundahl, Kiely M.spa
dc.creator.googleGlenn, Stuart B.spa
dc.creator.googleMiceli-Richard, Corinnespa
dc.creator.googleBowman, Simonspa
dc.creator.googleLester, Suespa
dc.creator.googleEriksson, Perspa
dc.creator.googleEloranta, Maija-Leenaspa
dc.creator.googleBrun, Johan G.spa
dc.creator.googleGøransson, Lasse G.spa
dc.creator.googleHarboe, Ernaspa
dc.creator.googleKaufman, Kenneth M.spa
dc.creator.googleKvarnström, Marikaspa
dc.creator.googleCunninghame Graham, Deborah S.spa
dc.creator.googlePatel, Ketanspa
dc.creator.googleAdler, Adam J.spa
dc.creator.googleFarris, A. Darisespa
dc.creator.googleBrennan, Michael T.spa
dc.creator.googleChodosh, Jamesspa
dc.creator.googleGopalakrishnan, Rajaramspa
dc.creator.googleWeisman, Michael H.spa
dc.creator.googleVenuturupalli, Swamyspa
dc.creator.googleWallace, Daniel J.spa
dc.creator.googleHefner, Kimberly S.spa
dc.creator.googleHouston, Glen D.spa
dc.creator.googleHuang, Andrew J. W.spa
dc.creator.googleHughes, Pamela J.spa
dc.creator.googleLewis, David M.spa
dc.creator.googleRadfar, Lidaspa
dc.creator.googleVista, Evan S.spa
dc.creator.googleContessa E., Edgarspa
dc.creator.googleRohrer, Michael D.spa
dc.creator.googleStone, Donald U.spa
dc.creator.googleVyse, Timothy J.spa
dc.creator.googleHarley, John B.spa
dc.creator.googleGaffney, Patrick M.spa
dc.creator.googleJames, Judith A.spa
dc.creator.googleTurner, Seanspa
dc.creator.googleAlevizos, Iliasspa
dc.creator.googleAnaya, Juan-Manuelspa
dc.creator.googleRhodus, Nelson L.spa
dc.creator.googleSegal, Barbara M.spa
dc.creator.googleMontgomery, Courtney G.spa
dc.creator.googleScofield, R. Halspa
dc.creator.googleKovats, Susanspa
dc.creator.googleMariette, Xavierspa
dc.creator.googleMariette, Xavierspa
dc.creator.googleRönnblom, Larsspa
dc.creator.googleWitte, Torstenspa
dc.creator.googleRischmueller, Maureenspa
dc.creator.googleWahren-Herlenius, Mariespa
dc.creator.googleOmdal, Roaldspa
dc.creator.googleJonsson, Rolandspa
dc.creator.googleNg, Wan-Faispa
dc.creator.googleNordmark, Gunnelspa
dc.creator.googleLessard, Christopher J.spa
dc.creator.googleSivils, Kathy L.spa
dc.date.accessioned2018-12-13T17:08:55Z
dc.date.available2018-12-13T17:08:55Z
dc.date.created2017
dc.date.issued2017
dc.description.abstractSjögren’s syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL= 6.05 × 10−14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta= 2.59 × 10−9; odds ratio = 0.75; 95% confidence interval = 0.66–0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease. © 2017 Public Library of Science. All Rights Reserved.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1371/journal.pgen.1006820
dc.identifier.issnISSN 1553-7390
dc.identifier.urihttp://repository.urosario.edu.co/handle/10336/18812
dc.language.isoengspa
dc.relation.citationIssueNo. 6
dc.relation.citationTitlePLoS Genetics
dc.relation.citationVolumeVol. 13
dc.relation.ispartofPLoS Genetics, ISSN: 1553-7390, Vol. 13/No. 6 (2017)spa
dc.relation.urihttps://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1006820&type=printablespa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.rights.cchttps://creativecommons.org/publicdomain/zero/1.0/spa
dc.rights.urihttps://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006820
dc.source.bibliographicCitationHelmick, C.G., Felson, D.T., Lawrence, R.C., Gabriel, S., Hirsch, R., Kwoh, C.K., Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I (2008) Arthritis Rheum, 58 (1), pp. 15-25. , 18163481spa
dc.source.instnameinstname:Universidad del Rosario
dc.source.reponamereponame:Repositorio Institucional EdocUR
dc.subject.keywordArticlespa
dc.subject.keywordFemalespa
dc.subject.keywordFemalespa
dc.subject.keywordHumansspa
dc.subject.keywordUn-explained visual losseng
dc.subject.keywordSilicone oil
dc.subject.keywordVitrectomy
dc.subject.keywordRetinal detachment
dc.subject.keywordMüller cells
dc.subject.keywordNeuronal apoptosis
dc.subject.keywordPotassium
dc.titleIdentification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferonsspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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