Association of Hypothalamic-Pituitary-Adrenal Axis-Related Polymorphisms with Stress in Asthmatic Children on Inhaled Corticosteroids

Objective: Long-term treatment of asthmatic children with low and moderate doses of inhaled corticosteroids (ICS) may result in mild adrenal suppression. Various associations have been shown between adrenal reactivity and single nucleotide polymorphisms (SNPs) related to the hypothalamic-pituitary-adrenal (HPA) axis. We aimed to investigate the genetic contribution of four HPA axis-related SNPs to the individual stress response when on ICS. Methods: The low dose Synacthen test was performed in 62 asthmatic children (43 males, median age 7.9 years) before and after 3 months of treatment with inhaled fluticasone (200 µg/day) or budesonide (400 µg/day). The SNPs determined were: rs1876828 and rs242941 in the corticotropin-releasing hormone receptor 1 (CRHR1) gene, T(-2C) in the promoter region of the melanocortin receptor 2 (MC2R) gene and BclI restriction fragment length polymorphsism in the glucocorticoid receptor (GR) gene. Results: Homozygotes for the variant rs242941 (TT) demonstrated a delayed cortisol response after treatment with ICS compared to heterozygotes (GT) (p = 0.033) and those with the wild-type (GG) genotype (p = 0.018). Homozygotes for the variant rs1876828 (AA) manifested lower baseline cortisol levels before treatment (p = 0.009) compared to the GG genotype and delayed cortisol response after treatment compared to the GA genotype (p = 0.05). BclI heterozygotes for the G allele (GC) demonstrated higher basal cortisol levels before and after treatment with ICS compared to homozygotes (CC) (p = 0.024, p = 0.018). Three SNP interactions were associated with serum cortisol levels. Conclusion: There is evidence of a contribution of HPA axis-related genetic variation to the stress response of asthmatic children on ICS. The clinical importance of this finding needs further elucidation.