Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells
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...
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| Format: | Article |
| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/89229 https://orcid.org/0000-0002-7887-4301 |
| _version_ | 1826208732751593472 |
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| author | Hu, Xinli Kim, Hyun Raj, Towfique Brennan, Patrick J. Trynka, Gosia Teslovich, Nikola Slowikowski, Kamil Chen, Wei-Min Onengut-Gumuscu, Suna Baecher-Allan, Clare De Jager, Philip L. Rich, Stephen S. Stranger, Barbara E. Brenner, Michael B. Raychaudhuri, Soumya |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Hu, Xinli Kim, Hyun Raj, Towfique Brennan, Patrick J. Trynka, Gosia Teslovich, Nikola Slowikowski, Kamil Chen, Wei-Min Onengut-Gumuscu, Suna Baecher-Allan, Clare De Jager, Philip L. Rich, Stephen S. Stranger, Barbara E. Brenner, Michael B. Raychaudhuri, Soumya |
| author_sort | Hu, Xinli |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T14:11:12Z |
| format | Article |
| id | mit-1721.1/89229 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:11:12Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/892292022-10-01T19:40:28Z Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells Hu, Xinli Kim, Hyun Raj, Towfique Brennan, Patrick J. Trynka, Gosia Teslovich, Nikola Slowikowski, Kamil Chen, Wei-Min Onengut-Gumuscu, Suna Baecher-Allan, Clare De Jager, Philip L. Rich, Stephen S. Stranger, Barbara E. Brenner, Michael B. Raychaudhuri, Soumya Harvard University--MIT Division of Health Sciences and Technology Hu, Xinli 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. National Institutes of Health (U.S.) (7T32HG002295-10) 2014-09-09T15:37:45Z 2014-09-09T15:37:45Z 2014-06 2014-02 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/89229 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. https://orcid.org/0000-0002-7887-4301 en_US http://dx.doi.org/10.1371/journal.pgen.1004404 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Hu, Xinli Kim, Hyun Raj, Towfique Brennan, Patrick J. Trynka, Gosia Teslovich, Nikola Slowikowski, Kamil Chen, Wei-Min Onengut-Gumuscu, Suna Baecher-Allan, Clare De Jager, Philip L. Rich, Stephen S. Stranger, Barbara E. Brenner, Michael B. Raychaudhuri, Soumya Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title_full | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title_fullStr | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title_full_unstemmed | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title_short | Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4[superscript +] Effector Memory T Cells |
| title_sort | regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in cd4 superscript effector memory t cells |
| url | http://hdl.handle.net/1721.1/89229 https://orcid.org/0000-0002-7887-4301 |
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