title: Association of hypothalamic-pituitary-adrenal axis-related polymorphisms with stress in asthmatic children on inhaled corticosteroids.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Allergy, Penteli Children's Hospital, Athens, Greece. mtsartsali@gmail.com
authors.forename: Lemonia
authors.initials: L
authors.lastname: Tsartsali
authors.forename: Marios
authors.initials: M
authors.lastname: Papadopoulos
authors.forename: Evagelia
authors.initials: E
authors.lastname: Lagona
authors.forename: Anastasios
authors.initials: A
authors.lastname: Papadimitriou
authors.forename: Christina
authors.initials: C
authors.lastname: Kanaka-Gantenbein
authors.forename: Eirini
authors.initials: E
authors.lastname: Louizou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kastania
authors.forename: Kostas N
authors.initials: KN
authors.lastname: Priftis
authors.forename: George
authors.initials: G
authors.lastname: Chrousos
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000235:genetics; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D000099052:CRF Receptor, Type 1
chemical_list: D000305:Adrenal Cortex Hormones; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D006854:Hydrocortisone