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

Abstract

SummaryBackgroundA serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression.MethodsWe 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.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).InterpretationOur 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.FundingDepartment of Health Chair in Pharmacogenetics.

Concerted variation of the 3′ regulatory region of Ig heavy chain and Gm haplotypes across human continental populations

“…Furthermore, the genomic region encompassing HS1.2 and IGHG3 overlaps entirely with a slightly larger region (90 kb, chr14:106150000–106240000) densely populated with a number of variable SNP sites associated to different phenotypes (Buck et al, ; Goris et al, ; Hawcutt et al, ; Sun et al, ). In particular, two of them were found to be associated with increased levels of Ig G in the cerebrospinal fluid as compared to serum, a hallmark of Multiple Sclerosis (Buck et al, ).…”

Clinical genetic testing in endocrinology: Current concepts and contemporary challenges

“…Furthermore, recent studies indicate considerable genetic variation in drug‐targeting sites of many G‐protein coupled receptors (GPCRs), which may provide an area of furtive research for the endocrine field . Likewise, another recent study demonstrated asthma patients carrying specific genetic variants in the PDGFR gene were at increased risk of steroid‐induced adrenal suppression . Thus, it is possible that genetic testing may not only be used to guide therapy but also to predict those at increased risk of adverse endocrine outcomes.…”

“…118 Likewise, another recent study demonstrated asthma patients carrying specific genetic variants in the PDGFR gene were at increased risk of steroid-induced adrenal suppression. 119 Thus, it is possible that genetic testing may not only be used to guide therapy but also to predict those at increased risk of adverse endocrine outcomes.…”

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“…For example, a recent genome-wide association study (see table 1) in children with asthma discovered a genetic variation in the platelet-derived growth factor D locus that increased the risk of adrenal suppression in response to steroid therapy 27. This finding will potentially enable risk stratification of patients for more intensive monitoring of adrenal function, as well as encourage use of alternative medications, for example, leukotriene antagonists or anti-IgE therapy in these patients where possible 27…”