Thorax 2012;67(Suppl 2):A1-A204 A17inter-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 FEV 1 response as the outcome measure. The aim of this study was twofold: (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.Abstract S31 Figure 1

Background A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression.Methods We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a randomeffects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. FindingsBetween November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10 -⁶), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7•32, 95% CI 3•15-16•99; p=5•8 × 10 -⁸). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3•86, 95% CI 1•19-12•50; p=0•02) and adult COPD (2•41, 1•10-5•28; p=0•03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5•89, 95% CI 2•97-11•68; p=4•3 × 10 -⁹; and 4•05, 2•00-8•21; p=3•5 × 10 -¹⁰).Interpretation Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively.