Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Hu, X, Kim, H, Raj, T, Brennan, PJ, Trynka, G, Teslovich, N, Slowikowski, K, Chen, W-M, Onengut, S, Baecher-Allan, C, De Jager, PL, Rich, SS, Stranger, BE, Brenner, MB, Raychaudhuri, S |
Journal | PLoS Genet |
Volume | 10 |
Issue | 6 |
Pages | e1004404 |
Date Published | 2014 Jun |
ISSN | 1553-7404 |
Keywords | Arthritis, Rheumatoid, Autoimmune Diseases, CD4-Positive T-Lymphocytes, Celiac Disease, Cell Proliferation, Diabetes Mellitus, Type 1, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Antigen, T-Cell |
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+ 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. |
URL | http://dx.plos.org/10.1371/journal.pgen.1004404 |
DOI | 10.1371/journal.pgen.1004404 |
Pubmed | |
Alternate Journal | PLoS Genet. |
PubMed ID | 24968232 |
PubMed Central ID | PMC4072514 |
Grant List | UL1 TR000430 / TR / NCATS NIH HHS / United States 1R01AR063759-01A1 / AR / NIAMS NIH HHS / United States T32 HG002295 / HG / NHGRI NIH HHS / United States TR01 AI097128 / AI / NIAID NIH HHS / United States R01 AR063759 / AR / NIAMS NIH HHS / United States 7T32HG002295-10 / HG / NHGRI NIH HHS / United States |
PLoS Genet DOI:10.1371/journal.pgen.1004404
Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.
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