Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.

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 random-effects 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. FINDINGS: Between 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. FUNDING: Department of Health Chair in Pharmacogenetics.

Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma.

OBJECTIVE: To examine serum cortisol responses to a simplified low-dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels. DESIGN: Early morning salivary cortisol and EMSCn samples were collected for three consecutive days. On day three, Synacthen 500 ng/1·73 m(2) was administered intravenously. Samples were collected at 0, 15, 25, 35 min. RESULTS: A total of 269 subjects (160 M: 109 F), median (range) age 10·0 (5·1-15·2) years were studied. Peak cortisol in the LDSST was <500 nmol/l in 101 subjects (37·5%) and <350 nmol/l in 12 subjects (4·5%). Basal cortisol correlated with peak cortisol: r = 0·55, (95% CI: 0·46, 0·63, P < 0·0001). Time at which peak cortisol concentration was achieved was significantly related to the value of peak cortisol (P < 0·0001), with higher cortisol peaks occurring later in the test and lower cortisol peaks occurring earlier. EMSC and EMSCn had no predictive value for the identification of patients with a peak cortisol <500 nmol/l. EMSCn was superior to EMSC in identifying patients with a peak cortisol <350 nmol/l: a minimum EMSCn cut-off value of 12·5 nmol/l gave a negative predictive value of 99·2% and positive predictive value of 30·1%. CONCLUSION: Our data illustrate that basal measures of cortisol are likely to be of value in screening populations for patients at greatest risk of adrenal crisis. EMSCn shows promise as a screening tool for the identification of patients with severe adrenal insufficiency.

Large ABCA3 and SFTPC deletions resulting in lung disease.

RATIONALE: Mutations in genes encoding proteins important in the function and metabolism of pulmonary surfactant are recognized causes of lung disease. Clinical genetic testing is available for these disorders, but children with phenotypes consistent with surfactant dysfunction and no identifiable mutations in the known causative genes have been reported. OBJECTIVES: To identify the mechanism(s) for lung disease in two children with the phenotype of surfactant dysfunction who had negative testing in clinical laboratories for gene mutations causing surfactant dysfunction. METHODS: Amplicons spanning multiple exons of candidate genes were generated by polymerase chain reaction and sequenced. MEASUREMENTS AND MAIN RESULTS: A 4,335-base deletion that included all of exon 12 of the gene encoding member A3 of the adenosine triphosphate-binding cassette transporter was identified in a full-term infant with respiratory failure. A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease. CONCLUSIONS: Large deletions are a cause of surfactant dysfunction disorders and may need to be sought for specifically in children whose phenotypes suggest these syndromes but in whom clinical genetic testing is unrevealing.

Secondary pulmonary hypertension.

Recent research has greatly improved our understanding of the pathophysiology of pulmonary hypertension. There is increasing recognition that pulmonary hypertension is an important complication of many childhood respiratory diseases including cystic fibrosis, interstitial lung diseases, upper airways obstruction and disorders of the respiratory muscles and chest wall. Chronic hypoxaemia and, in some cases, destruction of the vascular bed are the key factors. The clinical features of pulmonary hypertension are often overshadowed by those of the primary respiratory disease but newer imaging techniques allow earlier detection of this complication. This may be important in the future if new specific therapies for primary pulmonary hypertension are shown to be beneficial in secondary pulmonary hypertension. With some conditions, such as airways obstruction due to adenotonsillar hypertrophy, treating the underlying cause leads to rapid resolution of the hypertension. However, with most disorders, such as cystic fibrosis, management is focused on treating the lung disease intensively and correcting the chronic hypoxaemia with oxygen therapy, sometimes augmented by nasal mask ventilation. However, although several new selective therapies are effective in idiopathic pulmonary arterial hypertension, their role in secondary pulmonary hypertension remains unclear.

Qualitative study of young people's and parents' beliefs about childhood asthma.

BACKGROUND: Asthma continues to be a common childhood chronic illness managed principally in primary care. Self-management requires co-ordinated efforts of young people, carers and health professionals. Non-compliance occurs even when parents are supervising care, suggesting that decisions are made on the basis of beliefs that contrast with professional advice. Health professionals therefore need to understand the views of parents (or other carers) and patients to promote good self-management. Little attention has been given to carers' and young people's perspectives on asthma. AIM: To gain insights into the beliefs of a group of 25 young people aged nine to 16 years old and their carers about asthma and its management. DESIGN OF STUDY: Qualitative study using conversational-style interviews. SETTING: Generally deprived urban areas of Greater Manchester. METHOD: Interviews were conducted with 25 young people with asthma and separately with their carers. The interviews were analysed using the principles and procedures of grounded theory. RESULTS: Carers reported assessing asthma symptoms through observed effects on the child and other family members, including emotions and behaviours that disrupted family life. Young people emphasised the effect of asthma on their everyday lives and in particular the extent to which they appeared different to their peers. Some young people reported continuing symptoms and restrictions of activity that differed widely from the reports of their carers. CONCLUSION: Differences between young people's and carers' criteria for assessment suggest explanations for some 'non-compliant' behaviour. Carers' assessment of asthma severity through the absence of acute attacks is consistent with managing asthma as intermittent acute episodes. Professionals should take account of differences between young people's, carers' and professionals' perceptions of asthma.