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

Journal article

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.

Authors: Fairfax, B; Humburg, P; Makino, S; Naranbhai, V; Wong, D

• Publication status: Published
• Journal: Science (New York, N.Y.)
• Volume: 343
• Issue: 6175
• Pages: 1246949
• Publication date: 2014-03-01
• DOI: 10.1126/science.1246949
• EISSN: 1095-9203
• ISSN: 0036-8075
• Language: English
• Keywords: Genome-Wide Association Study; Interferon-gamma; Crohn Disease; Immunity, Innate; Indoleamine-Pyrrole 2,3,-Dioxygenase; Middle Aged; Cytochrome P-450 CYP1B1; Polymorphism, Single Nucleotide; CARD Signaling Adaptor Proteins; Genetic Variation; Monocytes; Interferon Regulatory Factor-2; Young Adult; Basic-Leucine Zipper Transcription Factors; Humans; Aryl Hydrocarbon Hydroxylases; Genetic Predisposition to Disease; Gene Expression Regulation; Interferon Regulatory Factors; Female; Adult; Quantitative Trait Loci; Male; Chromosome Mapping; Receptors, Purinergic P2; Antigens, CD14