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

Mark N. Lee; Chun Ye; Alexandra Chloé Villani; Towfique Raj; Weibo Li; Thomas M. Eisenhaure; Selina H. Imboywa; Portia I. Chipendo; F. Ann Ran; Kamil Slowikowski; Lucas D. Ward; Khadir Raddassi; Cristin McCabe; Michelle H. Lee; Irene Y. Frohlich; David A. Hafler; Manolis Kellis; Soumya Raychaudhuri; Feng Zhang; Barbara E. Stranger; Christophe O. Benoist; Philip L. De Jager; Aviv Regev; Nir Hacohen

doi:10.1126/science.1246980

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

Mark N. Lee, Chun Ye, Alexandra Chloé Villani, Towfique Raj, Weibo Li, Thomas M. Eisenhaure, Selina H. Imboywa, Portia I. Chipendo, F. Ann Ran, Kamil Slowikowski, Lucas D. Ward, Khadir Raddassi, Cristin McCabe, Michelle H. Lee, Irene Y. Frohlich, David A. Hafler, Manolis Kellis, Soumya Raychaudhuri, Feng Zhang, Barbara E. StrangerChristophe O. Benoist, Philip L. De Jager, Aviv Regev, Nir Hacohen

Research output: Contribution to journal › Article › peer-review

341 Scopus citations

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.

Original language	English
Article number	1246980
Journal	Science
Volume	343
Issue number	6175
DOIs	https://doi.org/10.1126/science.1246980
State	Published - 2014
Externally published	Yes

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Lee, M. N., Ye, C., Villani, A. C., Raj, T., Li, W., Eisenhaure, T. M., Imboywa, S. H., Chipendo, P. I., Ran, F. A., Slowikowski, K., Ward, L. D., Raddassi, K., McCabe, C., Lee, M. H., Frohlich, I. Y., Hafler, D. A., Kellis, M., Raychaudhuri, S., Zhang, F., ... Hacohen, N. (2014). Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science, 343(6175), Article 1246980. https://doi.org/10.1126/science.1246980

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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.",

author = "Lee, {Mark N.} and Chun Ye and Villani, {Alexandra Chlo{\'e}} and Towfique Raj and Weibo Li and Eisenhaure, {Thomas M.} and Imboywa, {Selina H.} and Chipendo, {Portia I.} and Ran, {F. Ann} and Kamil Slowikowski and Ward, {Lucas D.} and Khadir Raddassi and Cristin McCabe and Lee, {Michelle H.} and Frohlich, {Irene Y.} and Hafler, {David A.} and Manolis Kellis and Soumya Raychaudhuri and Feng Zhang and Stranger, {Barbara E.} and Benoist, {Christophe O.} and {De Jager}, {Philip L.} and Aviv Regev and Nir Hacohen",

year = "2014",

doi = "10.1126/science.1246980",

language = "English",

volume = "343",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6175",

}

Lee, MN, Ye, C, Villani, AC, Raj, T, Li, W, Eisenhaure, TM, Imboywa, SH, Chipendo, PI, Ran, FA, 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 2014, 'Common genetic variants modulate pathogen-sensing responses in human dendritic cells', Science, vol. 343, no. 6175, 1246980. https://doi.org/10.1126/science.1246980

TY - JOUR

T1 - Common genetic variants modulate pathogen-sensing responses in human dendritic cells

AU - Lee, Mark N.

AU - Ye, Chun

AU - Villani, Alexandra Chloé

AU - Raj, Towfique

AU - Li, Weibo

AU - Eisenhaure, Thomas M.

AU - Imboywa, Selina H.

AU - Chipendo, Portia I.

AU - Ran, F. Ann

AU - Slowikowski, Kamil

AU - Ward, Lucas D.

AU - Raddassi, Khadir

AU - McCabe, Cristin

AU - Lee, Michelle H.

AU - Frohlich, Irene Y.

AU - Hafler, David A.

AU - Kellis, Manolis

AU - Raychaudhuri, Soumya

AU - Zhang, Feng

AU - Stranger, Barbara E.

AU - Benoist, Christophe O.

AU - De Jager, Philip L.

AU - Regev, Aviv

AU - Hacohen, Nir

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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DO - 10.1126/science.1246980

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C2 - 24604203

AN - SCOPUS:84896759364

SN - 0036-8075

VL - 343

JO - Science

JF - Science

IS - 6175

M1 - 1246980

ER -

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

Abstract

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