Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells

• Published in: Science (American Association for the Advancement of Science) Vol. 343; no. 6175; p. 1119
• Main Authors: Lee, Mark N., Ye, Chun, Villani, Alexandra-Chloé, 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
• 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: 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
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1246980

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.