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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Public Library of Science (PLoS)
2019-12-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008528&type=printable |
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| author | Hadi Maazi Jaana A Hartiala Yuzo Suzuki Amanda L Crow Pedram Shafiei Jahani Jonathan Lam Nisheel Patel Diamanda Rigas Yi Han Pin Huang Eleazar Eskin Aldons J Lusis Frank D Gilliland Omid Akbari Hooman Allayee |
| author_facet | Hadi Maazi Jaana A Hartiala Yuzo Suzuki Amanda L Crow Pedram Shafiei Jahani Jonathan Lam Nisheel Patel Diamanda Rigas Yi Han Pin Huang Eleazar Eskin Aldons J Lusis Frank D Gilliland Omid Akbari Hooman Allayee |
| author_sort | Hadi Maazi |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-4a781df9584f4f87aed4bdb31ec4b1f8 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-4a781df9584f4f87aed4bdb31ec4b1f82025-08-20T02:00:46ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042019-12-011512e100852810.1371/journal.pgen.1008528A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity.Hadi MaaziJaana A HartialaYuzo SuzukiAmanda L CrowPedram Shafiei JahaniJonathan LamNisheel PatelDiamanda RigasYi HanPin HuangEleazar EskinAldons J LusisFrank D GillilandOmid AkbariHooman AllayeeAsthma 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008528&type=printable |
| spellingShingle | Hadi Maazi Jaana A Hartiala Yuzo Suzuki Amanda L Crow Pedram Shafiei Jahani Jonathan Lam Nisheel Patel Diamanda Rigas Yi Han Pin Huang Eleazar Eskin Aldons J Lusis Frank D Gilliland Omid Akbari Hooman Allayee A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity. PLoS Genetics |
| 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 |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1008528&type=printable |
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