PhD ceremony Ms. O.E.M. Savenije: Origins of asthma in childhood: an approach by longitudinal wheezing phenotypes

PhD ceremony: Ms. O.E.M. Savenije

Dissertation: Origins of asthma in childhood: an approach by longitudinal wheezing phenotypes

Promotor(s): prof. D.S. Postma, prof. G.H. Koppelman

Faculty: Medical Sciences

Classifications and prediction rules that aim to identify preschool children that will develop asthma are not useful in clinical practice. Our research of longitudinal patterns of wheeze in childhood showed that these patterns (longitudinal wheezing phenotypes) are similar between English and Dutch cohorts of children, and these phenotypes are differentially associated with sensitization, lung function and asthma in childhood.

Longitudinal wheezing phenotypes are further investigated in a genetic association study of the gene Interleukin-1 Receptor-like 1 (IL1RL1), and its pathway, the IL33-IL1RL1 pathway. IL1RL1 encodes for a membrane receptor on epithelial cells (and others), and is stimulated by Interleukin-33 (IL33), which results in allergic inflammation. DNA variants in IL33, IL1RL1 and IL1RAP are predominantly associated with longitudinal wheezing phenotypes and asthma, while DNA variants in other genes of the pathway were not associated with the outcomes. Longitudinal wheezing phenotypes that are related to sensitization and allergy were associated with DNA variants in this pathway, suggesting that DNA variance in the IL33-IL1RL1 pathway might play a role in the development of sensitization and allergy, resulting in wheeze.

Because wheeze is oscillation of air in a narrow tube, the relation is studied of a lung function parameter of smaller airways (FEF₅₀ level) and asthma. Lower FEF₅₀ was associated with more airway hyperresponsiveness, which is strongly related to asthma. Asthmatic children had less growth of FEF₅₀ than children without asthma. These findings indicate that smaller airways might play a role in asthma development.