Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells.

PLoS Genet
Authors
Keywords
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.

Year of Publication
2014
Journal
PLoS Genet
Volume
10
Issue
6
Pages
e1004404
Date Published
2014 Jun
ISSN
1553-7404
URL
DOI
10.1371/journal.pgen.1004404
PubMed ID
24968232
PubMed Central ID
PMC4072514
Links
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