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Hypothalamic-pituitary-adrenal axis suppression in asthma: A glucocorticoid receptor polymorphism may protect
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  • Wisdom Akurugu,
  • Carel van Heerden,
  • Nicola Mulder,
  • Ekkehard Zöllner
Wisdom Akurugu
University of Cape Town Faculty of Health Sciences

Corresponding Author:[email protected]

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Carel van Heerden
Stellenbosch University
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Nicola Mulder
University of Cape Town Faculty of Health Sciences
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Ekkehard Zöllner
Stellenbosch University
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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) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. Methods: DNA was extracted from saliva obtained from 95 asthmatic 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: The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response.
16 May 2020Submitted to Pediatric Allergy and Immunology
20 May 2020Reviewer(s) Assigned
05 Jun 2020Review(s) Completed, Editorial Evaluation Pending
08 Jun 2020Editorial Decision: Revise Major
24 Jul 20201st Revision Received
25 Jul 2020Review(s) Completed, Editorial Evaluation Pending
25 Jul 2020Reviewer(s) Assigned
10 Aug 2020Editorial Decision: Revise Minor
08 Sep 20202nd Revision Received
11 Sep 2020Review(s) Completed, Editorial Evaluation Pending
14 Sep 2020Editorial Decision: Accept
Feb 2021Published in Pediatric Allergy and Immunology volume 32 issue 2 on pages 273-279. 10.1111/pai.13379