Objectives:To identify genes associated with asthma exacerbations in European children with a reported use of ICS.
Methods:We performed a genome-wide association study (GWAS) meta-analysis across three European asthma cohorts (PACMAN, PASS and follow MAGICS)that participated in the Pharmacogenomics in Childhood Asthma consortium. We studied 1,204 asthmatic children treated with ICS. The primary outcome measure was asthma exacerbations, defined as the use of oral corticosteroids, asthma-related hospitalizations or asthma-related emergency room visits. Imputation of genetic variants was performed using the Haplotype Reference Consortium as reference panel by means of the Michigan Imputation Server. Association testing of 7.5 million genetic variants with minor allele frequency≥1% was per-formed using logistic regression models and results were meta-analyzed.
Results:A total of 74 genetic variants were suggestively associated with asthma exacerbations despite the use of ICS (p≤5×106). The most significant variants were located in 9 different loci (minimum p-value = 2.3 × 107), including one gene previously identified as associated with ICS response in Asian populations (ALLC). Additionally, novel associations were revealed in biologically plausible genes with drug metabolism functions and in genes belonging to the Wnt/β-catenin signaling pathway.
Conclusions: We identified several novel genes suggestively associated with asthma exacerbations despite the use of ICS. Validation will be performed in further independent studies.