Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression

• Published in: Science (American Association for the Advancement of Science) Vol. 343; no. 6175; p. 1118
• Main Authors: Fairfax, Benjamin P., Humburg, Peter, Makino, Seiko, Naranbhai, Vivek, Wong, Daniel, Lau, Evelyn, Jostins, Luke, Plant, Katharine, Andrews, Robert, McGee, Chris, Knight, Julian C.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 07.03.2014; The American Association for the Advancement of Science
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases - genetics; bacterial infections; Basic-Leucine Zipper Transcription Factors - genetics; CARD Signaling Adaptor Proteins - genetics; Chromosome Mapping; Chromosomes; Coding; Crohn Disease - epidemiology; Crohn Disease - genetics; Cytochrome P-450 CYP1B1; dendritic cells; Feedback (Response); Female; gene expression; Gene Expression Regulation - immunology; Gene mapping; genes; Genetic markers; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Genetics; Genome-Wide Association Study; genomics; health status; Humans; immune response; Immunity, Innate - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; innate immunity; Interferon Regulatory Factor-2 - genetics; Interferon Regulatory Factors - genetics; interferon-beta; Interferon-gamma - pharmacology; Lipopolysaccharide Receptors - immunology; Male; Middle Aged; monocytes; Monocytes - drug effects; Monocytes - immunology; Networks; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Receptors, Purinergic P2 - genetics; RESEARCH ARTICLE SUMMARY; Stimuli; Toll-like receptor 3; viral diseases of animals and humans; Young Adult
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1246949

It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by Gregersen ). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit a response to bacterial or viral infection and assess the functional links between genetic variants and profiles of gene expression. M. N. Lee et al. ( 10.1126/science.1246980 ) analyzed the expression of more than 400 genes, in dendritic cells from 30 healthy subjects, which revealed how expression quantitative trait loci (eQTLs) affect gene expression within the interferon-β and the Toll-like receptor 3 and 4 pathways. Fairfax et al. ( 10.1126/science.1246949 ) performed a genome-wide analysis to show that many eQTLs affected monocyte gene expression in a stimulus- or time-specific manner. Analysis of the transcriptional responses during induced innate immune activity in primary human monocytes is explained. [Also see Perspective by Gregersen ] 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.