We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity.
- Authors
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
- Abstract
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. Author summary: The genetic factors that modulate risk of asthma through gene-environment (GxE) interactions are poorly understood, due in large part to the inherent difficulties in carrying out such studies in humans. To address these challenges, we used the Hybrid Mouse Diversity Panel to elucidate the genetic architecture of asthma-related phenotypes in mice and identify loci that are associated with airway hyperreactivity (AHR) under control exposure conditions and in response to diesel exhaust particles (DEP), as a model traffic-related air pollutant. In the absence of exposure, we identified two loci on chromosomes 2 and 19 for AHR. The locus on chromosome 19 harbors Il33 and is syntenic to association signals observed for asthma at the IL33 locus in humans. In response to DEP exposure, we mapped AHR to a region on chromosome 3 and used a genetically modified mouse model to functionally demonstrate that Dapp1 is one of the genes underlying the GxE association at this locus. Collectively, our results support the concept 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.
- Subjects
AIR pollutants; AIR pollution; MUCOUS membranes; CONDITIONED response; CHROMOSOMES
- Publication
PLoS Genetics, 2019, Vol 15, Issue 12, pN.PAG
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1008528