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



Hawcutt, DB ORCID: 0000-0002-8120-6507, Francis, B ORCID: 0000-0002-2130-5976, Carr, D ORCID: 0000-0001-8028-4282, Jorgensen, AL, Yin, P, Wallin, N, O'Hara, NJ, Zhang, JE ORCID: 0000-0003-1813-2207, Bloch, KM, Ganguli, A
et al (show 9 more authors) (2018) Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study. The Lancet Respiratory Medicine, 6 (6). 442 - 450.

[img] Text
Figure1A.pdf - Accepted Version

Download (129kB)
[img] Text
Figure1B.pdf - Accepted Version

Download (35kB)
[img] Text
Figure1C.pdf - Accepted Version

Download (112kB)
[img] Text
Figure1D.pdf - Accepted Version

Download (34kB)
[img] Text
Figure2A.pdf - Accepted Version

Download (115kB)
[img] Text
Figure2B.pdf - Accepted Version

Download (34kB)
[img] Text
Figure2C.pdf - Accepted Version

Download (124kB)
[img] Text
Figure2D.pdf - Accepted Version

Download (36kB)
[img] Text
Figure3A.pdf - Accepted Version

Download (5kB)
[img] Text
Figure3B.pdf - Accepted Version

Download (5kB)
[img] Text
Figure5A_200218.pdf - Accepted Version

Download (4kB)
[img] Text
Figure5B_200218.pdf - Accepted Version

Download (5kB)
[img] Text
Supplementary Data Section response to reviewers v18.docx - Accepted Version

Download (266kB)
[img] Text
Hawcutt2018_LancetRespiratory.pdf - Published Version

Download (915kB)

Abstract

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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 16 Mar 2018 09:04
Last Modified: 27 Nov 2020 10:13
DOI: 10.1016/S2213-2600(18)30058-4
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3018926