dc.contributor.author | Hu, Xinli | |
dc.contributor.author | Kim, Hyun | |
dc.contributor.author | Raj, Towfique | |
dc.contributor.author | Brennan, Patrick J. | |
dc.contributor.author | Trynka, Gosia | |
dc.contributor.author | Teslovich, Nikola | |
dc.contributor.author | Slowikowski, Kamil | |
dc.contributor.author | Chen, Wei-Min | |
dc.contributor.author | Onengut-Gumuscu, Suna | |
dc.contributor.author | Baecher-Allan, Clare | |
dc.contributor.author | De Jager, Philip L. | |
dc.contributor.author | Rich, Stephen S. | |
dc.contributor.author | Stranger, Barbara E. | |
dc.contributor.author | Brenner, Michael B. | |
dc.contributor.author | Raychaudhuri, Soumya | |
dc.date.accessioned | 2014-09-09T15:37:45Z | |
dc.date.available | 2014-09-09T15:37:45Z | |
dc.date.issued | 2014-06 | |
dc.date.submitted | 2014-02 | |
dc.identifier.issn | 1553-7404 | |
dc.identifier.issn | 1553-7390 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/89229 | |
dc.description.abstract | Genome-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.sponsorship | National Institutes of Health (U.S.) (7T32HG002295-10) | en_US |
dc.language.iso | en_US | |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1371/journal.pgen.1004404 | en_US |
dc.rights | Creative Commons Attribution | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.source | Public Library of Science | en_US |
dc.title | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Hu, 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.department | Harvard University--MIT Division of Health Sciences and Technology | en_US |
dc.contributor.mitauthor | Hu, Xinli | en_US |
dc.relation.journal | PLoS Genetics | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dspace.orderedauthors | Hu, 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, Soumya | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-7887-4301 | |
mit.license | PUBLISHER_CC | en_US |
mit.metadata.status | Complete | |