Discovery of Gene-by-Air Pollution Interactions in Respiratory Disease using Genetically Diverse Mice with Validation in Humans

Our goal is to identify gene-environment interactions (GxE) with acute and chronic exposure to the ambient air pollutant ozone (O3) that contribute to common, chronic respiratory diseases like asthma and COPD. However, detecting GxE with O3 exposure in human epidemiologic studies is extremely challenging for a number of reasons, including statistical power and precision of exposure assessment. To overcome these challenges, we have exploited genetically diverse, multi-parental mouse populations, namely the Diversity Outbred (DO) and Collaborative Cross (CC, inbred), as GxE discovery platforms because in these models we can maximize information about both genetic variation and O3 exposure. Previously, we utilized the CC to identify a large-effect GxE quantitative trait loci (QTL) with acute O3 on chromosome (Chr) 15 that affected airway injury and inflammation. At this locus, two candidate genes emerged, Angpt1 and Rspo2. We also found that a common variant at the orthologous locus in humans (rs10086579, located between ANGPT1 and RSPO2) affected response to acute O3 in humans, demonstrating proof of concept for our approach. This variant also exhibited GxE with chronic air pollution in COPD, indicating it likely affects response to both acute and chronic exposure. Here, we propose to first identify the causal gene on Chr 15 in mice (Angpt1 vs. Rspo2), then identify new GxE QTL for both acute and chronic O3 responses. In all cases, we will translate our findings from mouse to human through targeted analysis of GxE with common variants in human orthologs of the genes we identify in mice using existing genotype and O3 exposure data from 3 human studies. The human studies include (1) an acute O3 challenge dataset (n=191) in which inflammation was quantified, (2) the Multi-Ethnic Study of Atherosclerosis Air Pollution Study (MESA-Air, n~6000) in which associations between chronic O3 exposure and COPD (emphysema and lung function) have been quantified, and (3) the Children’s Health Study (CHS, n~1800) in which associations between chronic O3 and childhood-onset asthma have been quantified. In Aim 1, we will evaluate Angpt1 and Rspo2 using knockdown/knockout and rescue experiments in mice. In parallel, we will conduct an expanded human genetic analysis of acute and chronic O3 response with rs10086579 and nearby variants using the 3 human datasets. In Aim 2, we will identify new GxE for acute O3 response in mice by performing a QTL mapping study involving two CC strains that are phenotypically divergent but not due to variation at the Chr 15 QTL. Gene expression QTL (eQTL) mapping in alveolar macrophages (AM) and mediation analysis will be used to identify candidate genes. We will then test for GxE in the human studies. In Aim 3, we will identify GxE for chronic O3 response using DO mice, employing a longitudinal study design in which lung function is measured prior to and after O3 exposure. After mapping QTL at high resolution and identifying candidate genes, we will test for GxE in the CHS and MESA-Air. In total, our work will reveal novel genes associated with that affect O3-induced asthma and COPD onset and/or progression. Project Number: 1R01ES036998-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Samir Kelada | Institution: UNIV OF NORTH CAROLINA CHAPEL HILL, CHAPEL HILL, NC | Award Amount: $3,082,011 | Activity Code: R01 | Study Section: Genetics of Health and Disease Study Section[GHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11234709