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A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity

Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-envir...

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Autores principales: Maazi, Hadi, Hartiala, Jaana A., Suzuki, Yuzo, Crow, Amanda L., Shafiei Jahani, Pedram, Lam, Jonathan, Patel, Nisheel, Rigas, Diamanda, Han, Yi, Huang, Pin, Eskin, Eleazar, Lusis, Aldons. J., Gilliland, Frank D., Akbari, Omid, Allayee, Hooman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944376/
https://www.ncbi.nlm.nih.gov/pubmed/31869344
http://dx.doi.org/10.1371/journal.pgen.1008528
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author Maazi, Hadi
Hartiala, Jaana A.
Suzuki, Yuzo
Crow, Amanda L.
Shafiei Jahani, Pedram
Lam, Jonathan
Patel, Nisheel
Rigas, Diamanda
Han, Yi
Huang, Pin
Eskin, Eleazar
Lusis, Aldons. J.
Gilliland, Frank D.
Akbari, Omid
Allayee, Hooman
author_facet Maazi, Hadi
Hartiala, Jaana A.
Suzuki, Yuzo
Crow, Amanda L.
Shafiei Jahani, Pedram
Lam, Jonathan
Patel, Nisheel
Rigas, Diamanda
Han, Yi
Huang, Pin
Eskin, Eleazar
Lusis, Aldons. J.
Gilliland, Frank D.
Akbari, Omid
Allayee, Hooman
author_sort Maazi, Hadi
collection PubMed
description Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10(-6)) and 19 (p = 5.6x10(-7)). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10(-6)). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans.
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spelling pubmed-69443762020-01-17 A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity Maazi, Hadi Hartiala, Jaana A. Suzuki, Yuzo Crow, Amanda L. Shafiei Jahani, Pedram Lam, Jonathan Patel, Nisheel Rigas, Diamanda Han, Yi Huang, Pin Eskin, Eleazar Lusis, Aldons. J. Gilliland, Frank D. Akbari, Omid Allayee, Hooman PLoS Genet Research Article Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10(-6)) and 19 (p = 5.6x10(-7)). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10(-6)). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans. Public Library of Science 2019-12-23 /pmc/articles/PMC6944376/ /pubmed/31869344 http://dx.doi.org/10.1371/journal.pgen.1008528 Text en © 2019 Maazi et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Maazi, Hadi
Hartiala, Jaana A.
Suzuki, Yuzo
Crow, Amanda L.
Shafiei Jahani, Pedram
Lam, Jonathan
Patel, Nisheel
Rigas, Diamanda
Han, Yi
Huang, Pin
Eskin, Eleazar
Lusis, Aldons. J.
Gilliland, Frank D.
Akbari, Omid
Allayee, Hooman
A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title_full A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title_fullStr A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title_full_unstemmed A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title_short A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity
title_sort gwas approach identifies dapp1 as a determinant of air pollution-induced airway hyperreactivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944376/
https://www.ncbi.nlm.nih.gov/pubmed/31869344
http://dx.doi.org/10.1371/journal.pgen.1008528
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