Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by Gregersen ). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit...
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| Published in | Science (American Association for the Advancement of Science) Vol. 343; no. 6175; p. 1119 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Association for the Advancement of Science
07.03.2014
The American Association for the Advancement of Science |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0036-8075 1095-9203 1095-9203 |
| DOI | 10.1126/science.1246980 |
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| Abstract | It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by
Gregersen
). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit a response to bacterial or viral infection and assess the functional links between genetic variants and profiles of gene expression.
M. N. Lee
et al.
(
10.1126/science.1246980
) analyzed the expression of more than 400 genes, in dendritic cells from 534 healthy subjects, which revealed how expression quantitative trait loci (eQTLs) affect gene expression within the interferon-β and the Toll-like receptor 3 and 4 pathways.
Fairfax
et al.
(
10.1126/science.1246949
) performed a genome-wide analysis to show that many eQTLs affected monocyte gene expression in a stimulus- or time-specific manner.
Mapping of human host-pathogen gene-by-environment interactions identifies pathogen-specific loci.
[Also see Perspective by
Gregersen
]
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. |
|---|---|
| AbstractList | 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
E. coli
lipopolysaccharide, influenza or interferon-β (IFNβ). We localized and validated causal variants to binding sites of pathogen-activated STAT and IRF transcription factors. We also identified a common variant in
IRF7
that is associated in
trans
with type I interferon induction in response to influenza infection. Our results reveal common alleles that explain inter-individual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases. 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. 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.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. It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by Gregersen ). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit a response to bacterial or viral infection and assess the functional links between genetic variants and profiles of gene expression. M. N. Lee et al. ( 10.1126/science.1246980 ) analyzed the expression of more than 400 genes, in dendritic cells from 534 healthy subjects, which revealed how expression quantitative trait loci (eQTLs) affect gene expression within the interferon-β and the Toll-like receptor 3 and 4 pathways. Fairfax et al. ( 10.1126/science.1246949 ) performed a genome-wide analysis to show that many eQTLs affected monocyte gene expression in a stimulus- or time-specific manner. Mapping of human host-pathogen gene-by-environment interactions identifies pathogen-specific loci. [Also see Perspective by Gregersen ] 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. Introduction; Variation in an individual's response to environmental factors is likely to influence susceptibility to complex human diseases. The genetic basis of such variation is poorly understood. Here, we identify natural genetic variants that underlie variation in the host innate immune response to infection and analyze the mechanisms by which such variants alter these responses.; Identifying the genetic basis of variability in the host response to pathogens. A cohort of 534 individuals donated blood for (a) genotyping of common DNA variants and (b) isolation of immune DCs. DCs were stimulated with viral and bacterial components, and the variability in individuals' gene expression responses was mapped to specific DNA variants, which were then shown to affect binding of particular transcription factors.; Methods; We derived dendritic cells (DCs) from peripheral blood monocytes of healthy individuals (295 Caucasians, 122 African Americans, 117 East Asians) and stimulated them with Escherichia coli lipopolysaccharide (LPS), influenza virus, or the cytokine interferon-β (IFN-β) to generate 1598 transcriptional profiles. We genotyped each of these individuals at sites of common genetic variation and identified the genetic variants that best explain variation in gene expression and gene induction between individuals. We then tested mechanistic predictions from these associations using synthetic promoter constructs and genome engineering.; Results; We identified 264 loci containing genetic variants associated with variation in absolute gene expression in human DCs, of which 121 loci were associated with variation in the induction of gene expression by one or more stimuli. Fine-mapping identified candidate causal single-nucleotide polymorphisms (SNPs) associated with expression variance, and deeper functional experiments localized three of these SNPs to the binding sites of stimulus-activated transcription factors. We also identified a cis variant in the transcription factor, IRF7, associated in trans with the induction of a module of antiviral genes in response to influenza infection. Of the identified genetic variants, 35 were also associated with autoimmune or infectious disease loci found by genome-wide association studies.; Discussion; The genetic variants we uncover and the molecular basis for their action provide mechanistic explanations and principles for how the innate immune response to pathogens and cytokines varies across individuals. Our results also link disease-associated variants to specific immune pathways in DCs, which provides greater insight into mechanisms underlying complex human phenotypes. Extending our approach to many immune cell types and pathways will provide a global map linking human genetic variants to specific immunological processes. [PUBLICATION ABSTRACT] It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by Gregersen). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit a response to bacterial or viral infection and assess the functional links between genetic variants and profiles of gene expression. M. N. Lee et al. (10.1126/science.1246980) analyzed the expression of more than 400 genes, in dendritic cells from 30 healthy subjects, which revealed how expression quantitative trait loci (eQTLs) affect gene expression within the interferon-β and the Toll-like receptor 3 and 4 pathways. Fairfax et al. (10.1126/science.1246949) performed a genome-wide analysis to show that many eQTLs affected monocyte gene expression in a stimulus- or time-specific manner. [PUBLICATION 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. [PUBLICATION ABSTRACT] Immune Variation It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective by Gregersen). Two studies now report on the effects of stimulating immunological monocytes and dendritic cells with proteins that can elicit a response to bacterial or viral infection and assess the functional links between genetic variants and profiles of gene expression. M. N. Lee et al. (10.1126/science.1246980) analyzed the expression of more than 400 genes, in dendritic cells from 30 healthy subjects, which revealed how expression quantitative trait loci (eQTLs) affect gene expression within the interferon-β and the Toll-like receptor 3 and 4 pathways. Fairfax et al. (10.1126/science.1246949) performed a genome-wide analysis to show that many eQTLs affected monocyte gene expression in a stimulus- or time-specific manner. |
| Author | Imboywa, Selina H. McCabe, Cristin Chipendo, Portia I. Lee, Mark N. Li, Weibo Villani, Alexandra-Chloé Hacohen, Nir Ye, Chun Frohlich, Irene Y. Regev, Aviv Raj, Towfique Lee, Michelle H. Raddassi, Khadir Slowikowski, Kamil Kellis, Manolis Raychaudhuri, Soumya Benoist, Christophe O. Ran, F. Ann Hafler, David A. Stranger, Barbara E. Eisenhaure, Thomas M. Ward, Lucas D. Zhang, Feng De Jager, Philip L. |
| AuthorAffiliation | 4 Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston MA 02115, USA 3 Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA 7 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA 10 Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, UK 1 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA 8 Department of Neurology, Yale School of Medicine, CT 06511, USA 11 McGovern Institute for Brain Research, MIT, Cambridge, MA, 02139, USA 14 Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637, USA 15 Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA 17 Howard Hughes Medical Institute 2 Harvard Medical School, Boston, MA 02115, USA 9 Divisions of Genetics and Rheumatol |
| AuthorAffiliation_xml | – name: 1 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA – name: 7 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – name: 16 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – name: 3 Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, MA 02129, USA – name: 13 Department of Biological Engineering, MIT, Cambridge, MA, 02139, USA – name: 15 Institute for Genomics and Systems Biology, The University of Chicago, Chicago, IL 60637, USA – name: 2 Harvard Medical School, Boston, MA 02115, USA – name: 4 Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston MA 02115, USA – name: 10 Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, UK – name: 11 McGovern Institute for Brain Research, MIT, Cambridge, MA, 02139, USA – name: 17 Howard Hughes Medical Institute – name: 12 Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, 02139, USA – name: 8 Department of Neurology, Yale School of Medicine, CT 06511, USA – name: 9 Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA – name: 14 Section of Genetic Medicine, The University of Chicago, Chicago, IL 60637, USA – name: 5 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA – name: 6 Bioinformatics and Integrative Genomics, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA |
| Author_xml | – sequence: 1 givenname: Mark N. surname: Lee fullname: Lee, Mark N. – sequence: 2 givenname: Chun surname: Ye fullname: Ye, Chun – sequence: 3 givenname: Alexandra-Chloé surname: Villani fullname: Villani, Alexandra-Chloé – sequence: 4 givenname: Towfique surname: Raj fullname: Raj, Towfique – sequence: 5 givenname: Weibo surname: Li fullname: Li, Weibo – sequence: 6 givenname: Thomas M. surname: Eisenhaure fullname: Eisenhaure, Thomas M. – sequence: 7 givenname: Selina H. surname: Imboywa fullname: Imboywa, Selina H. – sequence: 8 givenname: Portia I. surname: Chipendo fullname: Chipendo, Portia I. – sequence: 9 givenname: F. Ann surname: Ran fullname: Ran, F. Ann – sequence: 10 givenname: Kamil surname: Slowikowski fullname: Slowikowski, Kamil – sequence: 11 givenname: Lucas D. surname: Ward fullname: Ward, Lucas D. – sequence: 12 givenname: Khadir surname: Raddassi fullname: Raddassi, Khadir – sequence: 13 givenname: Cristin surname: McCabe fullname: McCabe, Cristin – sequence: 14 givenname: Michelle H. surname: Lee fullname: Lee, Michelle H. – sequence: 15 givenname: Irene Y. surname: Frohlich fullname: Frohlich, Irene Y. – sequence: 16 givenname: David A. surname: Hafler fullname: Hafler, David A. – sequence: 17 givenname: Manolis surname: Kellis fullname: Kellis, Manolis – sequence: 18 givenname: Soumya surname: Raychaudhuri fullname: Raychaudhuri, Soumya – sequence: 19 givenname: Feng surname: Zhang fullname: Zhang, Feng – sequence: 20 givenname: Barbara E. surname: Stranger fullname: Stranger, Barbara E. – sequence: 21 givenname: Christophe O. surname: Benoist fullname: Benoist, Christophe O. – sequence: 22 givenname: Philip L. surname: De Jager fullname: De Jager, Philip L. – sequence: 23 givenname: Aviv surname: Regev fullname: Regev, Aviv – sequence: 24 givenname: Nir surname: Hacohen fullname: Hacohen, Nir |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24604203$$D View this record in MEDLINE/PubMed |
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| Snippet | It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see the Perspective... Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and... Introduction; Variation in an individual's response to environmental factors is likely to influence susceptibility to complex human diseases. The genetic basis... Immune Variation It is difficult to determine the mechanistic consequences of context-dependent genetic variants, some of which may be related to disease (see... |
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| SubjectTerms | Adult Autoimmune Diseases - genetics Communicable Diseases Communicable Diseases - genetics dendritic cells Dendritic Cells - drug effects Dendritic Cells - immunology Deoxyribonucleic acid DNA E coli Environmental factors Environmental Influences Escherichia coli Feedback (Response) Female gene expression Gene mapping Gene-Environment Interaction genes Genetic diversity Genetic Loci Genetic variance genetic variation Genetics Genome-Wide Association Study HEK293 Cells Host-Pathogen Interactions - genetics Humans Immune response Infectious diseases Influenza A virus Interferon Regulatory Factor-7 - genetics interferon-beta Interferon-beta - pharmacology Lipopolysaccharides - immunology Logical Thinking Male Middle Aged monocytes Pathogens Polymorphism, Single Nucleotide Quantitative Trait Loci RESEARCH ARTICLE SUMMARY STAT Transcription Factors - genetics Stimuli Toll-like receptor 3 Transcriptome Young Adult |
| Title | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
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