Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression

Science. 2014 Mar 7;343(6175):1246949. doi: 10.1126/science.1246949.

Abstract

To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-γ (IFN-γ) or differing durations of lipopolysaccharide and mapped expression quantitative trait loci (eQTLs). More than half of cis-eQTLs identified, involving hundreds of genes and associated pathways, are detected specifically in stimulated monocytes. Induced innate immune activity reveals multiple master regulatory trans-eQTLs including the major histocompatibility complex (MHC), coding variants altering enzyme and receptor function, an IFN-β cytokine network showing temporal specificity, and an interferon regulatory factor 2 (IRF2) transcription factor-modulated network. Induced eQTL are significantly enriched for genome-wide association study loci, identifying context-specific associations to putative causal genes including CARD9, ATM, and IRF8. Thus, applying pathophysiologically relevant immune stimuli assists resolution of functional genetic variants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Basic-Leucine Zipper Transcription Factors / genetics
  • CARD Signaling Adaptor Proteins / genetics
  • Chromosome Mapping
  • Crohn Disease / epidemiology
  • Crohn Disease / genetics*
  • Cytochrome P-450 CYP1B1
  • Female
  • Gene Expression Regulation / immunology*
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Immunity, Innate / genetics*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Interferon Regulatory Factor-2 / genetics
  • Interferon Regulatory Factors / genetics
  • Interferon-gamma / pharmacology
  • Lipopolysaccharide Receptors / immunology
  • Male
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Receptors, Purinergic P2 / genetics
  • Young Adult

Substances

  • Basic-Leucine Zipper Transcription Factors
  • CARD Signaling Adaptor Proteins
  • CARD9 protein, human
  • IRF2 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interferon Regulatory Factor-2
  • Interferon Regulatory Factors
  • Lipopolysaccharide Receptors
  • NFE2L3 protein, human
  • P2RY11 protein, human
  • Receptors, Purinergic P2
  • indoleamine 2,3-dioxygenase 2, human
  • interferon regulatory factor-8
  • Interferon-gamma
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1