Air pollutant multiomics improves functional annotation of SNPs associated with lung disease

Particulate matter exposure impacts asthma and chronic obstructive pulmonary disease (COPD) outcomes, and this risk is expected to grow. Therapies that target disease and exposure risk mechanisms are necessary to address this concern. We identified airway epithelial transcriptional mechanisms associated with exposure and disease risk using a functional genomics pipeline that combined unbiased nascent RNA sequencing, genetic prioritization, and gene-regulatory element correlation. We then applied functional studies to prioritized regulatory elements and transcriptional mechanisms and established hyaluronic acid metabolism and TOMM7 regulation as plausible targets supported by airway models and primary human data. Our pipeline shifts the objectives of exposure and genetic studies from broad discovery to refining specific targets, which are more focused on therapeutic manipulation. While future studies are necessary to validate the targets, our framework integrates exposures, transcriptional biology, and human genetics to improve prioritization and streamline translation between target discovery and validation.