While progress has been made in identifying the genes and exposures related to lung function and asthma, the common susceptibility factors and critical pathways underlying these pathological processes are not well understood. For example, traffic-related pollutants have adverse effects on airway hyperreactivity (AHR), lung development, and asthma, and both genome-wide association study (GWAS) and candidate gene approaches have identified genetic variants associated with asthma-related phenotypes. However, there has been limited success in identifying genes that modulate susceptibility to environmental exposures. We propose to use an innovative genetics approach in mice and humans to identify novel variants that interact with traffic-related pollutant exposures to affect lung function phenotypes and the risk of childhood asthma.
In Specific Aim 1, we will characterize ~150 inbred and recombinant inbred mouse strains from the Hybrid Mouse Diversity Panel (HMDP) to determine their response to diesel exhaust particles (DEP) exposure, a model traffic-related pollutant. Lung function and AHR will be assessed using state-of-the-art plethysmography. In preliminary studies, we observe substantial variability among 8 HMDP strains characterized by this protocol, which is most likely attributable to naturally occurring genetic differences amongst these strains.
In Specific Aim 2, we will use the phenotype data from the HMDP and publicly available genotypes of ~130,000 single nucleotide polymorphisms to carry out a gene-environment (GxE) GWAS and identify loci exhibiting evidence for an interaction with DEP on lung function. Positional """"""""exposure-responsive"""""""" candidate genes and regions of interest will be prioritized for further evaluation using functional and bioinformatics experiments.
Specific Aim 3 will build on the mouse studies and use synteny mapping to identify loci that exhibit GxE interactions to affect asthma-related phenotypes in humans. In preliminary studies, we have carried out a GWAS and a GxE GWAS for traffic exposure and asthma in ~4000 subjects from the Children's Health Study (CHS). Leveraging these results and newly developed and innovative spatial temporal exposure models, we will use a two-stage design, with replication in an independent sample, to investigate whether loci of interest identified in th CHS GxE GWAS are supported by the results of the HMDP GxE GWAS and vice versa.
In Specific Aim 4, we will confirm the GxE interactions through in vivo studies. For each of two validated susceptibility loci in humans, we will use genotype data to recall 120 CHS subjects not part of the GWAS discovery sample who live in high (n=30) and low (n=30) areas of traffic-related pollution exposure levels and who are homozygous for the non- effect allele (n=30) and who carry at least one effect allele (n=30). These subjects will be phenotyped for AHR and lung function using standard spirometry protocols and assessed for clinical asthma status. The results of this integrative genomics approach in mice and humans will lead to a better understanding of how genes and environmental exposures interact to affect lung function phenotypes, which could have important clinical, epidemiological, and translational implications for the treatment of asthma.

Public Health Relevance

The overall goals of this project are to understand the relationship between asthma, genetic factors, and traffic- related pollution using a combination of mouse models and human populations. The results of these integrative genetics studies will lead to a better understanding of how genes and environmental exposures interact to affect lung function and asthma susceptibility, which could have important clinical, epidemiological, and translational implications for the development of novel treatment strategies.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Mcallister, Kimberly A
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University of Southern California
Public Health & Prev Medicine
Schools of Medicine
Los Angeles
United States
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Zhou, Hui; Li, Xia Iona; Kim, Jeong Hee et al. (2018) Effect of inhaled allergens and air pollutants on childhood rhinitis development. Ann Allergy Asthma Immunol 120:212-214
Olde Loohuis, Loes M; Mangul, Serghei; Ori, Anil P S et al. (2018) Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry 8:96
Li, Shengwen Calvin; Stucky, Andres; Chen, Xuelian et al. (2018) Single-cell transcriptomes reveal the mechanism for a breast cancer prognostic gene panel. Oncotarget 9:33290-33301
Alderete, T L; Song, A Y; Bastain, T et al. (2018) Prenatal traffic-related air pollution exposures, cord blood adipokines and infant weight. Pediatr Obes 13:348-356
Kothari, Parul H; Qiu, Weiliang; Croteau-Chonka, Damien C et al. (2018) Role of local CpG DNA methylation in mediating the 17q21 asthma susceptibility gasdermin B (GSDMB)/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression quantitative trait locus. J Allergy Clin Immunol 141:2282-2286.e6
Mangul, Serghei; Yang, Harry Taegyun; Strauli, Nicolas et al. (2018) ROP: dumpster diving in RNA-sequencing to find the source of 1 trillion reads across diverse adult human tissues. Genome Biol 19:36
Rahmani, Elior; Schweiger, Regev; Shenhav, Liat et al. (2018) BayesCCE: a Bayesian framework for estimating cell-type composition from DNA methylation without the need for methylation reference. Genome Biol 19:141
Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A et al. (2018) An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures. Genetics 209:685-698
Chen, Yan; Millstein, Joshua; Liu, Yao et al. (2018) Single-Cell Digital Lysates Generated by Phase-Switch Microfluidic Device Reveal Transcriptome Perturbation of Cell Cycle. ACS Nano 12:4687-4694
Hartiala, Jaana; Schwartzman, William S; Gabbay, Julian et al. (2017) The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities. Curr Atheroscler Rep 19:6

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