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

Hadi Maazi,Nisheel Patel,Pedram Shafiei Jahani,Yuzo Suzuki,Eleazar Eskin,Jaana A Hartiala,Pin Huang,Diamanda Rigas,Frank D Gilliland,Hooman Allayee,Jonathan Lam,Amanda L Crow,Yi Han,Aldons J Lusis,Omid Akbari,Gregory S Barsh

doi:10.1371/journal.pgen.1008528

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.

Highlights

Asthma is a complex disease characterized by chronic airway inflammation that affects over 300 million people worldwide [1]
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 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

Summary

Introduction

Asthma is a complex disease characterized by chronic airway inflammation that affects over 300 million people worldwide [1]. Despite the large numbers of loci identified to date, the risk alleles, most of which are common in the population, still only explain a small fraction (~7%) of asthma’s overall heritability [36, 37] This observation implies either the existence of additional variants with smaller effect sizes, rare susceptibility alleles, and/or higher order interactions between genes and environmental factors. While identification of genes is one important step towards improving our understanding of asthma pathogenesis, it does not provide direct information about interactions between genetic risk factors and environmental triggers. This is compounded by the inherent difficulties of carrying out gene-environment (GxE) interaction studies in humans. Accurate exposure assessments, adequately powered sample sizes in which genetic, phenotypic, and exposure data are all available, and the heterogeneous nature of asthma itself pose significant practical and technical hurdles that have yet to

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Conclusion