BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: PACMAN (n=357, age: 4-12 years, the Netherlands), BREATHE (n=820, age: 3-22 years, UK) and PAGES (n=391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signaling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the CAMP (clinical trial, n=172, age:5-12 years, USA), GALA II (n=745, age:8-21, USA) and PASS cohorts (n=391, age:5-18, UK) to test the robustness of the findings. Finally, all results were meta-analyzed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year,; OR=1.22 (p=0.013) and OR=1.22 (p=0.0017) respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a co-chaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signaling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults. This article is protected by copyright. All rights reserved.