Regulation of Gene Expression in Autoimmune Disease Loci and the Genetic Basis of Proliferation in CD4+ Effector Memory T Cells
Open accessAbstract
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+ TEM) cells in the pathogenesis of these diseases. To elucidate mechanisms of autoimmune disease alleles, we investigated molecular phenotypes in CD4+ effector memory T cells potentially affected by these variants. In a cohort of genotyped healthy individuals, we isolated high purity CD4+ TEM 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, rs389862A, increased proliferative response (p=4.75 × 10-8). 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+ TEM abundance or proliferation. Our study underscores the power of examining molecular phenotypes in relevant cells and conditions for understanding pathogenic mechanisms of disease variants.
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In a transcriptome study of CD4+ Effector Memory T cells, GRB10 was the most downregulated gene after T-cell receptor stimulation.
“Additionally, in a transcriptome study of CD4+ Effector Memory T cells, GRB10 was the most downregulated gene after T-cell receptor stimulation70.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [70]
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Quantifying the contribution of Neanderthal introgression to the heritability of complex traits
McArthur, E., Rinker, D. C., & Capra, J. A. (2021) · Nature Communications · doi:10.1038/s41467-021-24582-y · Cited by 71 · see citing works
- Authors
- Hu, X., Kim, H., Raj, T., Brennan, P. J., Trynka, G., Teslovich, N., Slowikowski, K., Chen, W.-M., Onengut, S., Baecher-Allan, C., De Jager, P. L., Rich, S. S., Stranger, B. E., Brenner, M. B., & Raychaudhuri, S.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- University of Virginia (US)
- University of Chicago (US)
- Corresponding author
- Raychaudhuri, Soumya
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-06-26
- Volume
- 10
- Issue
- 6
- Pages
- e1004404
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC4072514
- OpenAlex
- W1975528320
- Cited by
- 52
- References
- 36
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 1
- FWCI
- 3.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Knowledge@UChicago (University of Chicago) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion)
- University of Chicago (cc-by)
- Funders
- National Multiple Sclerosis Society
- Arthritis Foundation
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health (UL1TR000430, 1r01ar063759-01a1, 1R01‐AR‐063759)
- National Human Genome Research Institute (T32HG002295)
- National Institute of Allergy and Infectious Diseases (R01AI097128, TR01 AI097128)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (1R01AR063759-01A1, R01-AR063759)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- CD4+ effector memory T cells, gene expression regulation, cis-eQTL, rheumatoid arthritis, type 1 diabetes, celiac disease, single nucleotide polymorphisms, T cell proliferation, T cell receptor stimulation, disease risk alleles, transcriptional response
- MeSH terms
- Arthritis, Rheumatoid, Autoimmune Diseases, Celiac Disease, Diabetes Mellitus, Type 1, Gene Expression Regulation, Genotype, Humans, Phenotype, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Cell Proliferation, Genome-Wide Association Study
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