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Hypothalamic-pituitary-adrenal axis suppression in asthma: A glucocorticoid receptor polymorphism may protect
Wisdom Alemya Akurugu1, Carel Jacobus Van Heerden2, Nicola Mulder1
1Computational Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
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 subclassified according to their post-metyrapone adrenocorticotropin (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 = .021). √PMTP ACTH was associated with CC (effect size = 10.85, P = .005) and GC genotypes (effect size = 4.06, P = .023). The C allele is inherited as a dominant trait (effect size = -1.31 (95% CI -2.39--0.33; P = .012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; P-values .023 and <2 × 10-26 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.
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