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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.

Original publication

DOI

10.1126/science.1246949

Type

Journal article

Journal

Science

Publication Date

07/03/2014

Volume

343

Keywords

Adult, Antigens, CD14, Aryl Hydrocarbon Hydroxylases, Basic-Leucine Zipper Transcription Factors, CARD Signaling Adaptor Proteins, Chromosome Mapping, Crohn Disease, Cytochrome P-450 CYP1B1, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Immunity, Innate, Indoleamine-Pyrrole 2,3,-Dioxygenase, Interferon Regulatory Factor-2, Interferon Regulatory Factors, Interferon-gamma, Male, Middle Aged, Monocytes, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Receptors, Purinergic P2, Young Adult