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Abstract
Introduction Corticosteroids are the main stay of preventative therapy for asthma-related symptoms. There is a wide range of inter-patient variability both in terms of response to therapy, and suppression of the HPA axis leading to potentially fatal adrenal suppression. A recently undertaken GWAS identified the GLCCI1 variant rs37973 as a biomarker for corticosteroid efficacy using FEV1 response as the outcome measure. The aim of this study was two-fold: (a) to replicate the association with corticosteroid efficacy (using steroid dose and an increase in asthma exacerbations as surrogate measures) and (b) to determine whether the same variant is associated with adrenal suppression in asthmatic patients on inhaled corticosteroids.
Methods The study included data on 402 asthmatic children (age 5–18yrs), who were recruited to the Pharmacogenetics of Adrenal Suppression with inhaled Steroids (PASS) study, all of whom were on long term corticosteroid therapy (>6 months), and had a clinically indicated low dose short Synacthen test (LDSST). Detailed history of their medication use and exacerbations were recorded for the 6 months prior to LDSST. Regression models, adjusted for significant clinical factors, were used to test for association between the SNP and each outcome.
Results The rs37973 variant was associated with an increase in prescribed total inhaled/intranasal corticosteroid doses both before and after adjustment for body surface area. This association was significant when assuming both an additive mode of inheritance (p-value=0.020 for BSA adjusted total) as previously reported, and a recessive model (p-value =0.006 for BSA adjusted total). The variant was also associated with increased hospital admissions over the 6 month period (OR 2.16, 95% CI:1.10–4.33 when comparing homozygous states). There was no association with adrenal suppression (baseline or peak) or the number of rescue oral steroid courses.
Conclusion In the first replication study in a European population, we have shown that the rs37973 SNP is associated with increased corticosteroid dose and an increase in asthma-related hospital admissions, further supporting the evidence that GLCCI1 is a determinant of steroid efficacy in asthma. However, this SNP was not associated with steroid-induced adrenal suppression, divorcing efficacy from toxicity, at least with respect to this gene.
