title: Common genetic variants modulate pathogen-sensing responses in human dendritic cells.
abstract: 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.
authors.affiliation: Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Lee
authors.forename: Chun
authors.initials: C
authors.lastname: Ye
authors.forename: Alexandra-Chloé
authors.initials: AC
authors.lastname: Villani
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.forename: Weibo
authors.initials: W
authors.lastname: Li
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Eisenhaure
authors.forename: Selina H
authors.initials: SH
authors.lastname: Imboywa
authors.forename: Portia I
authors.initials: PI
authors.lastname: Chipendo
authors.forename: F Ann
authors.initials: FA
authors.lastname: Ran
authors.forename: Kamil
authors.initials: K
authors.lastname: Slowikowski
authors.forename: Lucas D
authors.initials: LD
authors.lastname: Ward
authors.forename: Khadir
authors.initials: K
authors.lastname: Raddassi
authors.forename: Cristin
authors.initials: C
authors.lastname: McCabe
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Lee
authors.forename: Irene Y
authors.initials: IY
authors.lastname: Frohlich
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.forename: Christophe O
authors.initials: CO
authors.lastname: Benoist
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics; D003141:Communicable Diseases / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004926:Escherichia coli; D005260:Female; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000235:genetics*; D006801:Humans; D009980:Influenza A virus; D050839:Interferon Regulatory Factor-7 / Q000235:genetics*; D016899:Interferon-beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D050791:STAT Transcription Factors / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
chemical_list: C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D008070:Lipopolysaccharides; D050791:STAT Transcription Factors; D016899:Interferon-beta