title: Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression.
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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Humburg
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Seiko
authors.initials: S
authors.lastname: Makino
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wong
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Lau
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Jostins
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Katharine
authors.initials: K
authors.lastname: Plant
authors.affiliation: Wellcome Trust Sanger Institute, University of Cambridge, Hinxton CB10 1SA, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Andrews
authors.affiliation: Wellcome Trust Sanger Institute, University of Cambridge, Hinxton CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: McGee
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics; D002874:Chromosome Mapping; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D050836:Interferon Regulatory Factor-2 / Q000235:genetics; D050835:Interferon Regulatory Factors / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018048:Receptors, Purinergic P2 / Q000235:genetics; D055815:Young Adult; D000099185:Interferon Regulatory Factor-8
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D050976:Basic-Leucine Zipper Transcription Factors; D053468:CARD Signaling Adaptor Proteins; D065633:Cytochrome P-450 CYP1B1; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D018950:Lipopolysaccharide Receptors; D018048:Receptors, Purinergic P2; D000099185:Interferon Regulatory Factor-8; C505855:CARD9 protein, human; C576711:IDO2 protein, human; C494229:IRF2 protein, human; C117963:NFE2L3 protein, human; C109734:P2RY11 protein, human; C585496:CYP1B1 protein, human