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

English version

Autoři: Hadi Maazi ^aff001; Jaana A. Hartiala ^aff002; Yuzo Suzuki ^aff001; Amanda L. Crow ^aff002; Pedram Shafiei Jahani ^aff001; Jonathan Lam ^aff001; Nisheel Patel ^aff001; Diamanda Rigas ^aff001; Yi Han ^aff002; Pin Huang ^aff002; Eleazar Eskin ^aff004; Aldons. J. Lusis ^aff005; Frank D. Gilliland ^aff002; Omid Akbari ^aff001; Hooman Allayee ^aff002
Působiště autorů: Departments of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ^aff001; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ^aff002; Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America ^aff003; Department of Computer Science and Inter-Departmental Program in Bioinformatics, University of California, Los Angeles, Los Angeles, California, United States of America ^aff004; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff005; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff006; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff007
Vyšlo v časopise: A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008528
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008528

Souhrn

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.

Klíčová slova:

Air pollution – Asthma – Genetic loci – Genetic predisposition – Genome-wide association studies – Human genetics – Inbred strains – Inhalation

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