A Narrative Review of Gene-Environment Interactions in Pediatric Pulmonology

Genetic and environmental factors are known to shape the onset, course, and outcomes of pediatric lung disease, yet interactions between these variables are rarely considered in clinical practice. Gene-environment (GxE) interactions occur when the combined effect of a genetic variant and an environmental exposure differs from what would be expected from combining the effect of either variable alone. Considering these interactions may reveal subgroups at heightened risk, explain apparent inconsistencies across studies, and highlight opportunities for targeted intervention. In this narrative review, we outline the conceptual basis of GxE interactions, including the importance of scale, centering, and timing. We summarize their implications and provide a high-level overview of available analytic strategies. We then examine disease-specific findings in asthma, cystic fibrosis, and bronchopulmonary dysplasia, highlighting how GxE processes can shape lung health from early life into adulthood and may contribute to chronic obstructive pulmonary disease risk. Across the asthma and cystic fibrosis examples presented here, commonly reported interactions involve genes related to host defense and oxidative stress biology, with effects that appear sensitive to exposure timing and developmental context. We conclude by identifying near-term priorities for improving rigor, mechanistic integration, and translation. Together, these insights frame pediatric lung disease within a life-course GxE model, emphasizing that genetic susceptibility and environmental risk should be considered jointly to improve outcomes.