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Science DOI:10.1126/science.1246980

Common genetic variants modulate pathogen-sensing responses in human dendritic cells.

Publication TypeJournal Article
Year of Publication2014
AuthorsLee, MN, Ye, C, Villani, A-C, Raj, T, Li, W, Eisenhaure, TM, Imboywa, SH, Chipendo, PI, F Ran, A, Slowikowski, K, Ward, LD, Raddassi, K, McCabe, C, Lee, MH, Frohlich, IY, Hafler, DA, Kellis, M, Raychaudhuri, S, Zhang, F, Stranger, BE, Benoist, CO, De Jager, PL, Regev, A, Hacohen, N
Date Published2014 Mar 07
KeywordsAdult, Autoimmune Diseases, Communicable Diseases, Dendritic Cells, Escherichia coli, Female, Gene-Environment Interaction, Genetic Loci, Genome-Wide Association Study, HEK293 Cells, Host-Pathogen Interactions, Humans, Influenza A virus, Interferon Regulatory Factor-7, Interferon-beta, Lipopolysaccharides, Male, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, STAT Transcription Factors, Transcriptome, Young Adult

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-β (IFN-β). 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.


Alternate JournalScience
PubMed ID24604203
PubMed Central IDPMC4124741
Grant ListR01 HG004037 / HG / NHGRI NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 AI091568 / AI / NIAID NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
DP1 CA174427 / CA / NCI NIH HHS / United States
F32 AG043267 / AG / NIA NIH HHS / United States
U19 AI082630 / AI / NIAID NIH HHS / United States
DP2 OD002230 / OD / NIH HHS / United States
DP1 MH100706 / MH / NIMH NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DP1 MH100706 / DP / NCCDPHP CDC HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
R01 DK097768 / DK / NIDDK NIH HHS / United States