ESPE Abstracts (2019) 92 P1-1

Could a Glucocorticoid Receptor Polymorphism be Protective against Hypothalamic-Pituitary-Adrenal Axis Suppression in Asthmatic Children on Corticosteroids?

Wisdom Alemya Akurugu1, Carel Jacobus Van Heerden2, Anna Alvera Vorster2, Maia Lesosky1, Nicola Mulder1, Ekkehard Werner Zöllner2

1University of Cape Town, Cape Town, South Africa. 2Stellenbosch University, Cape Town, South Africa

Background: Homozygotes for the single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) gene were previously associated with lower stimulated and basal cortisol levels respectively in asthmatic children on inhaled corticosteroids. Heterozygotes for rs41423247 of the glucocorticoid receptor (NR3C1) gene were found to have higher basal cortisol levels.

Objectives: To determine whether the SNPs rs242941 and rs1876828 of the CRHR1, and rs41423247 of the NR3C1 gene are associated with hypothalamic-pituitary-adrenal suppression (HPAS) in asthmatic school children on corticosteroids.

Methods: DNA was extracted from saliva obtained from 96 asthmatic children, 5.2-15.6 years old, treated with inhaled and nasal corticosteroids, who had previously undergone basal cortisol (C) and metyrapone testing. HPAS was diagnosed if C was <83 nmol/l or the post-metyrapone ACTH (PACTH) level <106 pg/ml. Thirty-six children were classified as suppressed. Non-suppressed children were sub-classified according to their PACTH into a middle (106-319 pg/ml) and a high (>319 pg/ml) ACTH response group, comprising 29 and 31 subjects respectively. TaqMan PCR assays were utilized for genotyping. ANOVA, linear, logistic and multinomial logistic regression analysis were performed.

Results: Only rs41423247 was associated with HPAS (P = 0.005). Mean difference of PACTH of the CC compared to GG genotype was 278.5 (19.5-537) pg/ml while the difference of GC compared to GG genotype was 143.5 (11.6-275.5) pg/ml; (P=0.030 and 0.032 respectively). The C allele of this SNP is less likely to be associated with HPAS (odds ratio [OR] = 0.38 [0.18-0.82]) and appears to be dominant (OR = 0.33 [0.13-0.83]). On linear regression, the effect was both additive (b = 137.7, SE = 42.7, P = 0.002) and dominant (b = 162.0, SE = 53.0, P = 0.003). Dominance was confirmed on logistic regression (P = 0.032).

Conclusions: rs41423247 (CC) of the NR3C1 gene was associated with higher PACTH levels and is less likely to be associated with HPAS.

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