Publication Date:
2014-03-08
Description:
To systematically investigate the impact of immune stimulation upon regulatory variant activity, we exposed primary monocytes from 432 healthy Europeans to interferon-gamma (IFN-gamma) 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-beta 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064786/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064786/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fairfax, Benjamin P -- Humburg, Peter -- Makino, Seiko -- Naranbhai, Vivek -- Wong, Daniel -- Lau, Evelyn -- Jostins, Luke -- Plant, Katharine -- Andrews, Robert -- McGee, Chris -- Knight, Julian C -- 074318/Wellcome Trust/United Kingdom -- 088891/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 281824/European Research Council/International -- 98082/Medical Research Council/United Kingdom -- G1001708/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Mar 7;343(6175):1246949. doi: 10.1126/science.1246949.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24604202" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Antigens, CD14/immunology
;
Aryl Hydrocarbon Hydroxylases/genetics
;
Basic-Leucine Zipper Transcription Factors/genetics
;
CARD Signaling Adaptor Proteins/genetics
;
Chromosome Mapping
;
Crohn Disease/epidemiology/*genetics
;
Cytochrome P-450 CYP1B1
;
Female
;
Gene Expression Regulation/*immunology
;
*Genetic Predisposition to Disease
;
Genetic Variation
;
Genome-Wide Association Study
;
Humans
;
Immunity, Innate/*genetics
;
Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
;
Interferon Regulatory Factor-2/genetics
;
Interferon Regulatory Factors/genetics
;
Interferon-gamma/pharmacology
;
Male
;
Middle Aged
;
Monocytes/drug effects/*immunology
;
Polymorphism, Single Nucleotide
;
Quantitative Trait Loci
;
Receptors, Purinergic P2/genetics
;
Young Adult
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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