TY - JOUR
T1 - Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression
AU - Fairfax, Benjamin P.
AU - Humburg, Peter
AU - Makino, Seiko
AU - Naranbhai, Vivek
AU - Wong, Daniel
AU - Lau, Evelyn
AU - Jostins, Luke
AU - Plant, Katharine
AU - Andrews, Robert
AU - McGee, Chris
AU - Knight, Julian C.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84896742056
U2 - 10.1126/science.1246949
DO - 10.1126/science.1246949
M3 - Article
C2 - 24604202
AN - SCOPUS:84896742056
SN - 0036-8075
VL - 343
JO - Science
JF - Science
IS - 6175
M1 - 1246949
ER -