ESPEYB15 8 Adrenals Important for Clinical Practice (5 abstracts)
8.6 Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study
Hawcutt DB , Francis B , Carr DF , Jorgensen AL , Yin P , Wallin N , O'Hara N , Zhang EJ , Bloch KM , Ganguli A , Thompson B , McEvoy L , Peak M , Crawford AA , Walker BR , Blair JC , Couriel J , Smyth RL & Pirmohamed M
Department of Women’s and Children’s Health, University of Liverpool, Liverpool, UK; Wolfson Centre for Personalised Medicine, Medical Research Council (MRC) Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
To read the full abstract: Lancet Respir Med. 2018 Mar 15. pii: S2213-2600(18)30058-4
Inhaled corticosteroids (ICS) are recommended for adults and children with asthma, as well as for chronic obstructive pulmonary disease (COPD). Although ICS are generally well-tolerated and have fewer systemic adverse effects than oral corticosteroids, some patients still develop systemic adverse effects. Adrenal suppression is a clinically important adverse effect, particularly in children with asthma, in whom its diagnosis can be challenging because presentation may range from asymptomatic biochemical changes to non-specifc lethargy to florid adrenal crisis and death. Inter-individual variation in susceptibility to adrenal suppression is striking, however, its etiology remains unclear, given that clinical factors account for only a small proportion of the variance (9). This is the first pharmacogenomic study to investigate the association between a patient’s genotype and corticosteroid-induced adrenal suppression. A polymorphism in the PDGFD gene locus was identified in a cohort of children with asthma in a genome-wide association study and found to be associated with adrenal suppression. This finding was validated in another paediatric asthma cohort and in a cohort of adults with chronic obstructive pulmonary disorder (COPD). A meta-analysis of the cohorts showed genome-wide significance.
Platelet-derived growth factors (PDGFs) direct the migration, differentiation, and function of various specialised mesenchymal cell types. PDGF receptors are required for development of steroid-producing cells in many organs, including the testes, ovaries, and adrenal cortex. Moreover, PDGFD is highly expressed in human adrenal gland, unlike PDGFA, PDGFB, and PDGFC, and the expression of PDGFD correlates negatively with cortisol secretion in adrenocortical adenomas. These data support the idea of a link between inter-individual variation in susceptibility to corticosteroid-induced adrenal suppression and a patient’s genotype, potentially through variation in the PDGFD gene locus. In addition, they offer the potential to develop translational pathways to prevent corticosteroid-induced adrenal suppression, thereby improving the benefit–risk ratio of this important therapy.
9. Hawcutt DB, Jorgensen AL, Wallin N, Thompson B, Peak M, Lacy D, Newland P, Didi M, Couriel J, Blair J, Pirmohamed M, Smyth RL. Adrenal responses to a low-dose short synacthen test in children with asthma. Clin Endocrinol (Oxf). 2015; 82(5): 648-56.
Volume 15
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ESPE Yearbook of Paediatric Endocrinology
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