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Tyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits

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dc.contributor.authorDiogo, Dorothée
dc.contributor.authorBastarache, Lisa
dc.contributor.authorLiao, Katherine P.
dc.contributor.authorGraham, Robert R.
dc.contributor.authorFulton, Robert S.
dc.contributor.authorGreenberg, Jeffrey D.
dc.contributor.authorEyre, Steve
dc.contributor.authorBowes, John
dc.contributor.authorCui, Jing
dc.contributor.authorLee, Annette
dc.contributor.authorPappas, Dimitrios A.
dc.contributor.authorKremer, Joel M.
dc.contributor.authorBarton, Anne
dc.contributor.authorCoenen, Marieke J. H.
dc.contributor.authorFranke, Barbara
dc.contributor.authorKiemeney, Lambertus A.
dc.contributor.authorMariette, Xavier
dc.contributor.authorRichard-Miceli, Corrine
dc.contributor.authorCanhao, Helena
dc.contributor.authorFonseca, João Eurico
dc.contributor.authorde Vries, Niek
dc.contributor.authorTak, Paul P.
dc.contributor.authorCrusius, J. Bart A.
dc.contributor.authorNurmohamed, Michael T.
dc.contributor.authorKurreeman, Fina
dc.contributor.authorMikuls, Ted R.
dc.contributor.authorOkada, Yukinori
dc.contributor.authorStahl, Eli A.
dc.contributor.authorLarson, David E.
dc.contributor.authorDeluca, Tracie L.
dc.contributor.authorO'Laughlin, Michelle
dc.contributor.authorFronick, Catrina C.
dc.contributor.authorFulton, Lucinda L.
dc.contributor.authorKosoy, Roman
dc.contributor.authorRansom, Michael
dc.contributor.authorBhangale, Tushar R.
dc.contributor.authorOrtmann, Ward
dc.contributor.authorCagan, Andrew
dc.contributor.authorGainer, Vivian
dc.contributor.authorKarlson, Elizabeth W.
dc.contributor.authorKohane, Isaac
dc.contributor.authorMurphy, Shawn N.
dc.contributor.authorMartin, Javier
dc.contributor.authorZhernakova, Alexandra
dc.contributor.authorKlareskog, Lars
dc.contributor.authorPadyukov, Leonid
dc.contributor.authorWorthington, Jane
dc.contributor.authorMardis, Elaine R.
dc.contributor.authorSeldin, Michael F.
dc.contributor.authorGregersen, Peter K.
dc.contributor.authorBehrens, Timothy
dc.contributor.authorRaychaudhuri, Soumya
dc.contributor.authorDenny, Joshua C.
dc.contributor.authorPlenge, Robert M.
dc.date.accessioned2022-05-25T15:33:49Z
dc.date.available2022-05-25T15:33:49Z
dc.date.issued2015
dc.descriptionCopyright: © 2015 Diogo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.pt_PT
dc.description.abstractDespite the success of genome-wide association studies (GWAS) in detecting a large number of loci for complex phenotypes such as rheumatoid arthritis (RA) susceptibility, the lack of information on the causal genes leaves important challenges to interpret GWAS results in the context of the disease biology. Here, we genetically fine-map the RA risk locus at 19p13 to define causal variants, and explore the pleiotropic effects of these same variants in other complex traits. First, we combined Immunochip dense genotyping (n = 23,092 case/control samples), Exomechip genotyping (n = 18,409 case/control samples) and targeted exon-sequencing (n = 2,236 case/controls samples) to demonstrate that three protein-coding variants in TYK2 (tyrosine kinase 2) independently protect against RA: P1104A (rs34536443, OR = 0.66, P = 2.3 x 10(-21)), A928V (rs35018800, OR = 0.53, P = 1.2 x 10(-9)), and I684S (rs12720356, OR = 0.86, P = 4.6 x 10(-7)). Second, we show that the same three TYK2 variants protect against systemic lupus erythematosus (SLE, Pomnibus = 6 x 10(-18)), and provide suggestive evidence that two of the TYK2 variants (P1104A and A928V) may also protect against inflammatory bowel disease (IBD; P(omnibus) = 0.005). Finally, in a phenome-wide association study (PheWAS) assessing >500 phenotypes using electronic medical records (EMR) in >29,000 subjects, we found no convincing evidence for association of P1104A and A928V with complex phenotypes other than autoimmune diseases such as RA, SLE and IBD. Together, our results demonstrate the role of TYK2 in the pathogenesis of RA, SLE and IBD, and provide supporting evidence for TYK2 as a promising drug target for the treatment of autoimmune diseases.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS One. 2015 Apr 7;10(4):e0122271pt_PT
dc.identifier.doi10.1371/journal.pone.0122271pt_PT
dc.identifier.eissn1932-6203
dc.identifier.urihttp://hdl.handle.net/10451/53176
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLoSpt_PT
dc.relation.publisherversionhttps://journals.plos.org/plosone/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleTyk2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traitspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue4pt_PT
oaire.citation.titlePLoS ONEpt_PT
oaire.citation.volume10pt_PT
person.familyNameCanhao
person.familyNameFonseca
person.givenNameHelena
person.givenNameJoão
person.identifier.ciencia-idF310-B85D-57C7
person.identifier.orcid0000-0002-3239-2809
person.identifier.orcid0000-0003-1432-3671
person.identifier.scopus-author-id6602393492
person.identifier.scopus-author-id7101983519
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication48f3be39-37f9-44de-9c7e-22e49a89efe5
relation.isAuthorOfPublication1772dc12-7c55-4c76-ae2d-c23270172480
relation.isAuthorOfPublication.latestForDiscovery48f3be39-37f9-44de-9c7e-22e49a89efe5

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