Perturbation of metabolic pathways mediates the association of air pollutants with asthma and cardiovascular diseases

Background: Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratoryand cardiovascular diseases, suggesting the involvement of common altered molecular pathways.Objectives: The goal was to find intermediate metabolites or metabolic pathways that could be associated withboth air pollutants and health outcomes (“meeting-in-the-middle”), thus shedding light on mechanisms andreinforcing causality.Methods: We applied a statistical approach named ‘meet-in-the-middle’ to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio-cerebrovascular diseases(CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways.Results: A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26,2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentiallymediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolismpathway was associated with air pollution exposure, AOA and CCVD. Conclusions: Our results suggest common pathway perturbations may occur as a consequence of chronic exposureto air pollution leading to increased risk for both AOA and CCVD.