Elucidation of the role of obesity and air pollution in the asthma etiology in adults

Non-communicable disease (NCD) epidemic threatens public health in all regions of the world. Asthma is one of the major NCDs along with cardiovascular diseases, cancer, diabetes, and other chronic respiratory diseases. Asthma etiology is poorly understood, hindering the efficient primary prevention. Recent findings indicate that asthma is a mixture of various phenotypes with potentially different mechanism. While obesity and air pollution have been indicated as risk factors for asthma, it is not clear yet whether they contribute to the development of asthma rather than exacerbation of already existing disease and through which mechanisms they exert the effects on asthma development. Elucidation of such mechanism, especially if it is shared by multiple exposures and/or multiple diseases, will critically benefit primary prevention. The research efforts for mechanistic understanding can be contextualized as part of exposome — the entirety of the exposures an individual experiences throughout the life course — and aging phenome — the diseases and morbidities often accompanied with aging — research, where systems approach e.g. omics analysis finds a critical usage.
The Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) is an on-going population cohort since 1991. With its detailed information on the participants' health, life style, and exposure, SAPALDIA offers a unique opportunity to investigate the NCD etiology. This PhD project aimed to contribute to better understanding the role of obesity and air pollution exposure in asthma etiology, taking the heterogeneity of the disease phenotype into account.
We identified four asthma phenotypes using latent class analysis, which showed heterogeneity in the association with obesity. We conducted epigenomics — assessments of genome-wide DNA methylation — and metabolomics — assessments of the entirety ofsmall molecules — on the blood samples taken from the adult-onset asthma cases and controls. Epigenomics pathway analysis revealed that DNA methylation on the inflammation-related genes modifies the effect of BMI on non-atopic adult-onset asthma. This pathway analysis also provided evidence that the NLRP3-IL1B-IL17 axis, a component of innate immunity, plays a role in the asthma etiology in humans, confirming the previous research findings in mice experiments. Metabolomics pathway analysis pointed to the perturbation of inflammatory pathways as a potentially shared mechanism through which long-term air pollution exposure affects adult-onset asthma and cardio- and cerebrovascular diseases.
Despite the cross-sectional study design and the limited statistical power, this PhD project achieved to demonstrate the importance of distinguishing asthma phenotypes to study etiology; to exemplify the usefulness of cohort studies with biobanks in exposome research and the applicability of systems approach in cohort studies; and to provide a proof-of-concept evidence of the disease mechanism shared by multiple NCDs. Our findings can be considered as the first step of the translational approach — innovation, validation, and application. Once validated by future research including replication in other populations and consolidation of causality using Mendelian randomization, the pursuit of mechanistic understanding can guide prevention strategies to efficiently tackle the NCD epidemic.