Functional Variant Discovery Identifies SPRY2 as a Genetic Mechanism Linking Wood Smoke with Asthma

As a consequence of climate change and land use policies, there has been a historic rise in wildfire smoke across the United States and the world. While the deleterious effects of wildfire smoke and associated air pollution on asthma outcomes are established epidemiologically, genetic risks and molecular mechanisms of how wildfire smoke affects asthma are unknown. This knowledge gap hinders the identification of high-risk individuals and the creation of targeted therapies or recommendations to protect these individuals. We identified 52 genetic risk variants that colocalized with genomic responses to wood smoke particles (WSP), a model of wildfire particulate matter, and associated with asthma in the Genetic Epidemiology Research on Aging (GERA) cohort. We used additional filters to prioritize variants for direct testing of allele-dependent transcriptional regulatory function in plasmid reporters. We found that the rs3861144 variant (Odds Ratio _asthma = 1.036) changes SPRY2 responses to WSP airway epithelial cells, which we showed is involved in mechanical scratch repair in cell culture by regulating Extracellular Signal-related Kinase (ERK) phosphorylation. These findings provide insights into the molecular pathways through which WSP may influence asthma risk and propose genetic candidates that warrant further study for their potential as clinical tools for asthma.