Precision medicine in childhood asthma The role of genetic variations in treatment response

Inhaled corticosteroids (ICS) have been the mainstay treatment for persistent asthma in children for decades. However, despite their high efficacy, there is substantial inter- and intra-individual variability in treatment response to ICS. Suboptimal asthma control might lead to persistent asthma symptoms and/or asthma exacerbations.
The main focus of this thesis was to identify genetic variations that could explain the heterogeneity in response to ICS predominantly in the concept of asthma exacerbations. For this purpose, we have used candidate gene and Genome Wide Association (GWA) study approaches, using data from clinical trials and cohorts that participated in the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Furthermore, we investigated which clinical/environmental factors and (pharmaco) genetic markers were associated with an increased risk of exacerbations in children with regular use of ICS using data of the PACMAN cohort. Finally, we carried out an economic evaluation to examine if a pharmacogenomic-guided strategy to prevent exacerbations is cost-effective for asthmatic children who need a step up from low dose ICS. For this purpose, we performed a cost-effectiveness study by comparing ADRB2-guided treatment (rs1042713) to the standard treatment before starting long-acting beta2 agonists (LABA). This genetic variant is the most consistently replicated variation in pharmacogenomics studies of LABA. Overall, we applied a multi-disciplinary approach by combining pharmacogenomics, epidemiology and cost-effectiveness studies.