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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 (New York, N.Y.)

Publication Date

03/2014

Volume

343

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

Keywords

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