Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells
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 c...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2015
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| Online Access: | http://hdl.handle.net/1721.1/96695 https://orcid.org/0000-0003-2782-2509 https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0002-8017-809X |
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| author | Lee, M. N. Ye, C. Villani, A.-C. Raj, T. Li, W. Eisenhaure, Thomas Imboywa, S. H. Chipendo, P. I. Slowikowski, K. Raddassi, K. McCabe, C. Lee, M. H. Frohlich, I. Y. Raychaudhuri, S. Stranger, B. E. Benoist, Christophe De Jager, Philip L. Hacohen, Nir Ran, F. Ann Zhang, Feng Regev, Aviv Hafler, David A. Ward, Lucas D. Kellis, Manolis |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Lee, M. N. Ye, C. Villani, A.-C. Raj, T. Li, W. Eisenhaure, Thomas Imboywa, S. H. Chipendo, P. I. Slowikowski, K. Raddassi, K. McCabe, C. Lee, M. H. Frohlich, I. Y. Raychaudhuri, S. Stranger, B. E. Benoist, Christophe De Jager, Philip L. Hacohen, Nir Ran, F. Ann Zhang, Feng Regev, Aviv Hafler, David A. Ward, Lucas D. Kellis, Manolis |
| author_sort | Lee, M. N. |
| collection | MIT |
| 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-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. |
| first_indexed | 2024-09-23T12:40:02Z |
| format | Article |
| id | mit-1721.1/96695 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:40:02Z |
| publishDate | 2015 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/966952022-09-28T09:17:36Z Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells Lee, M. N. Ye, C. Villani, A.-C. Raj, T. Li, W. Eisenhaure, Thomas Imboywa, S. H. Chipendo, P. I. Slowikowski, K. Raddassi, K. McCabe, C. Lee, M. H. Frohlich, I. Y. Raychaudhuri, S. Stranger, B. E. Benoist, Christophe De Jager, Philip L. Hacohen, Nir Ran, F. Ann Zhang, Feng Regev, Aviv Hafler, David A. Ward, Lucas D. Kellis, Manolis Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science McGovern Institute for Brain Research at MIT Zhang, Feng Ran, F. Ann Regev, Aviv Hafler, David A. Ward, Lucas D. Kellis, Manolis 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. National Human Genome Research Institute (U.S.) (Grant P50 HG006193) National Institutes of Health (U.S.). Pioneer Award (DP1 CA174427) Howard Hughes Medical Institute National Institutes of Health (U.S.) (Grant HG004037) National Institutes of Health (U.S.). Pioneer Award (DP1 MH100706) National Institutes of Health (U.S.) (Transformative R01 Grant R01 DK097768) W. M. Keck Foundation McKnight Foundation Merkin, Richard N. Damon Runyon Cancer Research Foundation Searle Scholars Program Simons Foundation 2015-04-22T15:43:50Z 2015-04-22T15:43:50Z 2014-03 2013-10 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/96695 Lee, M. N., C. Ye, A.-C. Villani, T. Raj, W. Li, T. M. Eisenhaure, S. H. Imboywa, et al. “Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells.” Science 343, no. 6175 (March 6, 2014): 1246980–1246980. https://orcid.org/0000-0003-2782-2509 https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0002-8017-809X en_US http://dx.doi.org/10.1126/science.1246980 Science Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Lee, M. N. Ye, C. Villani, A.-C. Raj, T. Li, W. Eisenhaure, Thomas Imboywa, S. H. Chipendo, P. I. Slowikowski, K. Raddassi, K. McCabe, C. Lee, M. H. Frohlich, I. Y. Raychaudhuri, S. Stranger, B. E. Benoist, Christophe De Jager, Philip L. Hacohen, Nir Ran, F. Ann Zhang, Feng Regev, Aviv Hafler, David A. Ward, Lucas D. Kellis, Manolis Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title_full | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title_fullStr | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title_full_unstemmed | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title_short | Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells |
| title_sort | common genetic variants modulate pathogen sensing responses in human dendritic cells |
| url | http://hdl.handle.net/1721.1/96695 https://orcid.org/0000-0003-2782-2509 https://orcid.org/0000-0001-8567-2049 https://orcid.org/0000-0002-8017-809X |
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