Genetic factors involved in the response to inhaled corticosteroids in pediatric asthma

Abstract

Inhaled corticosteroids (ICS) are the most commonly prescribed and effective medication to control asthma symptoms in children and young adults. High variability in the response to this treatment has been described among individuals and populations. These differences have been suggested to be the result of the interaction of several factors, including an important contribution of the individual’s genetic composition. However, the genetic markers of ICS response identified to date are not able to predict the responsiveness to this medication in clinical practice. This doctoral thesis aimed to identify genetic variants involved in the response to asthma treatment with ICS through genomic approaches. A systematic review of the main findings of the genomic studies of asthma susceptibility and treatment response published between 2016 and 2018 was performed, identifying the genetic markers to be followed up for replication. Two genome-wide association studies of asthma exacerbations despite ICS use in admixed and European populations were also completed, revealing two suggestive novel associations. Additionally, a gene-set enrichment analysis in asthma patients of European descent revealed a potential novel drug for asthma. Genetic associations with the change in lung function after a short period of ICS therapy were assessed, suggesting a novel association of a locus that could be involved in the response to this medication. Finally, the combination of transcriptomic data from different cell types with genomic information from asthma patients treated with ICS led to the identification of an additional potential novel locus for ICS response. The findings of this doctoral thesis suggest the existence of genetic markers of asthma treatment response specific to certain ancestry groups and shared among different populations. Moreover, the information about asthma exacerbations was evidenced as a good predictor of the response to this medication through the validation of previous associations described for different measures of ICS response.