Adrenal insufficiency and ICS: genetics takes a breath
Authors: Michael H Cho, Kelan G Tantisira
Journal: The Lancet Respiratory Medicine (2018)

Inhaled corticosteroids (ICS) have fundamentally changed the management of patients with asthma and play an important part in the management of chronic obstructive pulmonary disease (COPD)—the two most common chronic lung diseases.1GBD 2015 Chronic Respiratory Disease CollaboratorsGlobal, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet Respir Med. 2017; 5: 691-706Summary Full Text Full Text PDF PubMed Scopus (1381) Google Scholar These drugs are generally safe, but one of their most concerning side-effects is adrenal insufficiency, which can result in weakness, poor growth, hypoglycaemia, hypotension, and death. Although clinically evident adrenal insufficiency is rare, particularly in adults,2Lapi F Kezouh A Suissa S Ernst P The use of inhaled corticosteroids and the risk of adrenal insufficiency.Eur Respir J. 2013; 42: 79-86Crossref PubMed Scopus (42) Google Scholar, 3Patel L Wales J Kibirige M et al.Symptomatic adrenal insufficiency during inhaled corticosteroid treatment.Arch Dis Child. 2001; 85: 330-334Crossref PubMed Scopus (114) Google Scholar biochemical evidence of hypothalamic-pituitary-adrenal axis suppression—particularly in children—is not.4Smith RW Downey K Gordon M et al.Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid.Paediatr Child Health. 2012; 17: e34-e39Crossref PubMed Scopus (35) Google Scholar Recommendations have focused on screening for adrenal axis insufficiency in any child taking high daily doses of ICS, or a child taking ICS with other systemically absorbed corticosteroids. However, hypothalamic-pituitary-adrenal axis suppression can occur even with standard doses of ICS;5Kapadia CR Nebesio TD Myers SE et al.Endocrine effects of inhaled corticosteroids in children.JAMA Pediatr. 2016; 170: 163-170Crossref PubMed Scopus (62) Google Scholar the reasons for this variability in response are not clear. The pronounced growth in genetic studies, particularly genome-wide association studies, has led to identification of genetic associations with thousands of phenotypes, including response to and adverse effects from drugs—a field known as pharmacogenetics. In The Lancet Respiratory Medicine, Daniel Hawcutt and colleagues report an investigation into genetic variation as a potential contributor to risk of adrenal suppression, as measured by a low-dose synacthen test.6Hawcutt DB Francis B Carr DF et al.Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study.Lancet Respir Med. 2018; (published online March 15.)http://dx.doi.org/10.1016/S2213-2600(18)30058-4Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar In children with asthma using ICS as part of their treatment, a significant association was noted between adrenal suppression and a single nucleotide polymorphism (SNP) at the PDGFD gene locus (rs591118; discovery odds ratio [OR] 7·32, 95% CI 3·15–16·99; p=5·8 × 10−8). This study was small by comparison with traditional genome-wide association studies, with only 35 cases for one of the primary outcomes. Small sample sizes and case-control imbalance can increase the possibility of both type 1 and type 2 errors,7Ma C Blackwell T Boehnke M Scott LJ Recommended joint and meta-analysis strategies for case-control association testing of single low-count variants.Genet Epidemiol. 2013; 37: 539-550Crossref PubMed Scopus (93) Google Scholar, 8Sham PC Purcell SM Statistical power and significance testing in large-scale genetic studies.Nat Rev Genet. 2014; 15: 335-346Crossref PubMed Scopus (367) Google Scholar and these factors could have caused some of the signals which were subsequently filtered out by the investigators. After the filtering process, the rs591118 SNP near PDGFD was selected for replication in two validation cohorts—a paediatric asthma cohort and an adult COPD cohort. Results were significant in these two cohorts (respectively, OR 3·86, 95% CI 1·19–12·50; p=0·02; and 2·41, 1·10–5·28; p=0·03), and a meta-analysis combining all samples reached genome-wide significance. By contrast with most individual findings from genome-wide association studies, but more common in pharmacogenomic studies,9Maranville JC Cox NJ Pharmacogenomic variants have larger effect sizes than genetic variants associated with other dichotomous complex traits.Pharmacogenomics J. 2016; 16: 388-392Crossref PubMed Scopus (41) Google Scholar the effect size of Hawcutt and colleagues' finding was substantial, suggesting that the variant in PDGFD could have clinical implications. However, several issues should be considered before proceeding to a marker-stratified clinical trial or widespread recommendations for screening. First, the result was only genome-wide significant in the meta-analysis so additional replication would be ideal. Although finding an additional cohort of sufficient size might not be possible, an alternative resource is the growing number of biobanks with drug data linked to clinical outcomes, including cases of adrenal insufficiency in hundreds of thousands of individuals. External validation of the PDGFD variant as a potential biomarker is crucial in individuals of non-European ancestry, because allele frequencies of the associated variant are widely divergent in other ancestral populations. Second, among the top loci that were identified by the genome-wide analysis, Hawcutt and colleagues chose PDGFD in part because of biological evidence that this gene has a role in adrenal function. However, whether the reported variant affects PDGFD or some other gene is not known. We do not know the function of most variants in the human genome; in fact, evidence to date indicates that the gene nearest the genetic variant of interest (eg, PDGFD) is—in most cases—not the effector gene.10Visscher PM Wray NR Zhang Q et al.10 years of GWAS discovery: biology, function, and translation.Am J Hum Genet. 2017; 101: 5-22Summary Full Text Full Text PDF PubMed Scopus (1611) Google Scholar Third, patients in this study were selected based on clinical suspicion of adrenal insufficiency, and many participants received rescue doses or were on chronic oral corticosteroids. Furthermore, the effect sizes in the two validation cohorts—probably a more accurate estimate of the true effect—were modest. The relation between steroid dosing, adrenal suppression, and genetic variation should be examined further, with implications for generalisability to patients with decreased suspicion of adrenal suppression. Although the current study by Hawcutt and colleagues focuses specifically on adrenal-related insufficiency as a pharmacogenomic outcome, it begins to answer a question: what is the role of genetics in explaining how innate cortisol interacts with exogenous corticosteroids to affect a variety of effector and adverse outcomes, such as inflammatory response, diurnal variation, bone mineral density and growth?11Tantisira KG Lake S Silverman ES et al.Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.Hum Mol Genet. 2004; 13: 1353-1359Crossref PubMed Scopus (282) Google Scholar, 12Park H-W Ge B Tse S et al.Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts.J Allergy Clin Immunol. 2015; 136: 1240-1246Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar Since corticosteroids remain prominent in the treatment of various diseases, the biological and translational implications of studies such as this one are broad. It is an exciting time in genetics; researchers on larger and more diverse studies are finding and replicating thousands of associations, identifying new biology, and (more commonly in aggregate,10Visscher PM Wray NR Zhang Q et al.10 years of GWAS discovery: biology, function, and translation.Am J Hum Genet. 2017; 101: 5-22Summary Full Text Full Text PDF PubMed Scopus (1611) Google Scholar but also individually) obtaining results with the potential for risk prediction. The vision of using genetics to personalise therapy in obstructive lung disease is one step closer to reality. MHC declares grants from the National Heart, Lung, and Blood Institute relevant to this work, and GlaxoSmithKilne outside of the submitted work. KGT declares no competing interests. Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association studyOur 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. Full-Text PDF Open Access