Author responsible for correspondence
EW Zöllner
Faculty of Health Sciences
Department of Paediatrics and Child Health
Stellenbosch University
PO Box 241
Cape Town
8000
South Africa
Word count : 2480
Word count abstract: 250
Title character count : 99
No of tables: 5
No of figures: 1
Conflict of interest
WAA, CJVH, NM & EWZ have nothing to disclose.
Financial support
This study was supported by grants from the National Research Foundation and the South African Thoracic Society.
Abstract and keywords
Background: Asthmatic children on corticosteroids can develop hypothalamic-pituitary-adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) genewere associated with lower stimulated cortisol (F) levels,whereas rs41423247 of the glucocorticoid receptor (NR3C1) genewas associated with higher basal F levels. The objective of the current study was to confirmwhether these three SNPs are associated with HPAS in asthmatic children.
Methods: DNA was extracted from saliva obtained from 95asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty-six children were classified as suppressed. Non-suppressed children were sub-classified according to their post-metyrapone ACTH (PMTP ACTH)level into a middle (106-319 pg/ml) and a high (>319 pg/ml) ACTH response group. TaqMan®polymerase chain reaction assays were utilized.
Results: Only rs41423247 was inversely associated with HPAS (OR = 0.27 [95% CI 0.06-0.90]). Its GC genotype was inversely associated with HPAS (log odds = - 1.28, p = 0.021). √PMTP ACTH was associated with CC (effect size = 10.85, p = 0.005) and GC genotypes (effect size = 4.06, p = 0.023). The C allele is inherited as a dominant trait (effect size = -1.31 (95% CI -2.39 – -0.33; p = 0.012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; p-values 0.023 and < 2x10-26 for GC and CC respectively).
Conclusions: TheC allele of rs41423247was found to be protective against HPAS. CC genotype is associated with the highest PMTPACTH response.
Key words: Asthma, hypothalamus, pituitary, adrenal, polymorphism, receptors, glucocorticoids, steroids/adverse events, adrenal insufficiency, pituitary-adrenal-function tests
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