Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells

PLoS Genet. 2017 Mar 1;13(3):e1006643. doi: 10.1371/journal.pgen.1006643. eCollection 2017 Mar.


Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13.2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.

Publication types

  • Comparative Study

MeSH terms

  • Autoimmune Diseases / genetics*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Chromosome Mapping / methods
  • Diabetes Mellitus, Type 1 / genetics
  • Gene Expression Regulation
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Genotype
  • HEK293 Cells
  • Humans
  • Interferon Regulatory Factor-1 / genetics
  • Interleukin-27 / genetics
  • Mutation
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics*
  • Ribosomal Proteins / genetics
  • STAT1 Transcription Factor / genetics


  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Interleukin-27
  • RPS26 protein, human
  • Ribosomal Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human

Grant support

This work was supported by the University of Tartu for the Center of Translational Genomics (SP1GVARENG) [AM], Estonian Research Council grants IUT20-60 [AM] and IUT2-2 [PP], the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012, [AM], EU H2020 grant ePerMed (grant no. 692145, [AM], EU FP7 grant BBMRI-LPC (grant no 313010, [AM], ERA-Net.Rus grant EGIDA [PP], Wellcome Trust (Grants 074318 [JCK], and 090532/Z/09/Z [core facilities WTCHG]), the European Research Council (FP7/2007-2013; ERC Grant agreement number 281824 [JCK], Medical Research Council (98082 [JCK]), and National Institute for Health Research Oxford Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.