Publication Date:
2014-03-08
Description:
Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-beta (IFN-beta). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124741/" 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/PMC4124741/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Mark N -- Ye, Chun -- Villani, Alexandra-Chloe -- Raj, Towfique -- Li, Weibo -- Eisenhaure, Thomas M -- Imboywa, Selina H -- Chipendo, Portia I -- Ran, F Ann -- Slowikowski, Kamil -- Ward, Lucas D -- Raddassi, Khadir -- McCabe, Cristin -- Lee, Michelle H -- Frohlich, Irene Y -- Hafler, David A -- Kellis, Manolis -- Raychaudhuri, Soumya -- Zhang, Feng -- Stranger, Barbara E -- Benoist, Christophe O -- De Jager, Philip L -- Regev, Aviv -- Hacohen, Nir -- DP1 CA174427/CA/NCI NIH HHS/ -- DP1 MH100706/DP/NCCDPHP CDC HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- DP2 OD002230/OD/NIH HHS/ -- F32 AG043267/AG/NIA NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- R01 AI091568/AI/NIAID NIH HHS/ -- R01 AR063759/AR/NIAMS NIH HHS/ -- R01 DK097768/DK/NIDDK NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- RC2 GM093080/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32 HG002295/HG/NHGRI NIH HHS/ -- U19 AI082630/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Mar 7;343(6175):1246980. doi: 10.1126/science.1246980.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24604203" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Autoimmune Diseases/genetics
;
Communicable Diseases/genetics
;
Dendritic Cells/drug effects/*immunology
;
Escherichia coli
;
Female
;
*Gene-Environment Interaction
;
Genetic Loci
;
Genome-Wide Association Study
;
HEK293 Cells
;
Host-Pathogen Interactions/*genetics
;
Humans
;
Influenza A virus
;
Interferon Regulatory Factor-7/*genetics
;
Interferon-beta/pharmacology
;
Lipopolysaccharides/immunology
;
Male
;
Middle Aged
;
Polymorphism, Single Nucleotide
;
Quantitative Trait Loci
;
STAT Transcription Factors/*genetics
;
Transcriptome
;
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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