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dc.contributor.authorHu, Xinli
dc.contributor.authorKim, Hyun
dc.contributor.authorRaj, Towfique
dc.contributor.authorBrennan, Patrick J.
dc.contributor.authorTrynka, Gosia
dc.contributor.authorTeslovich, Nikola
dc.contributor.authorSlowikowski, Kamil
dc.contributor.authorChen, Wei-Min
dc.contributor.authorOnengut-Gumuscu, Suna
dc.contributor.authorBaecher-Allan, Clare
dc.contributor.authorDe Jager, Philip L.
dc.contributor.authorRich, Stephen S.
dc.contributor.authorStranger, Barbara E.
dc.contributor.authorBrenner, Michael B.
dc.contributor.authorRaychaudhuri, Soumya
dc.date.accessioned2014-09-09T15:37:45Z
dc.date.available2014-09-09T15:37:45Z
dc.date.issued2014-06
dc.date.submitted2014-02
dc.identifier.issn1553-7404
dc.identifier.issn1553-7390
dc.identifier.urihttp://hdl.handle.net/1721.1/89229
dc.description.abstractGenome-wide association studies (GWAS) and subsequent dense-genotyping of associated loci identified over a hundred single-nucleotide polymorphism (SNP) variants associated with the risk of rheumatoid arthritis (RA), type 1 diabetes (T1D), and celiac disease (CeD). Immunological and genetic studies suggest a role for CD4-positive effector memory T (CD[superscript +] T[subscript EM]) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4[superscript +] effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4[superscript +] T[subscript EM] cells from peripheral blood, then assayed relative abundance, proliferation upon T cell receptor (TCR) stimulation, and the transcription of 215 genes within disease loci before and after stimulation. We identified 46 genes regulated by cis-acting expression quantitative trait loci (eQTL), the majority of which we detected in stimulated cells. Eleven of the 46 genes with eQTLs were previously undetected in peripheral blood mononuclear cells. Of 96 risk alleles of RA, T1D, and/or CeD in densely genotyped loci, eleven overlapped cis-eQTLs, of which five alleles completely explained the respective signals. A non-coding variant, rs389862[superscript A], increased proliferative response (p = 4.75×10[superscript −8]). In addition, baseline expression of seventeen genes in resting cells reliably predicted proliferative response after TCR stimulation. Strikingly, however, there was no evidence that risk alleles modulated CD4[superscript +] T[subscript EM] abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (7T32HG002295-10)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pgen.1004404en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourcePublic Library of Scienceen_US
dc.titleRegulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cellsen_US
dc.typeArticleen_US
dc.identifier.citationHu, Xinli, Hyun Kim, Towfique Raj, Patrick J. Brennan, Gosia Trynka, Nikola Teslovich, Kamil Slowikowski, et al. “Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells.” Edited by Derry C. Roopenian. PLoS Genet 10, no. 6 (June 26, 2014): e1004404.en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.contributor.mitauthorHu, Xinlien_US
dc.relation.journalPLoS Geneticsen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsHu, Xinli; Kim, Hyun; Raj, Towfique; Brennan, Patrick J.; Trynka, Gosia; Teslovich, Nikola; Slowikowski, Kamil; Chen, Wei-Min; Onengut, Suna; Baecher-Allan, Clare; De Jager, Philip L.; Rich, Stephen S.; Stranger, Barbara E.; Brenner, Michael B.; Raychaudhuri, Soumyaen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-7887-4301
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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