title: Single nucleotide polymorphisms and type of steroid impact the functional response of the human glucocorticoid receptor.
abstract: BACKGROUND
  Clinical trials evaluating the use of steroids in septic shock have shown variable outcomes. Our previous studies have implicated human glucocorticoid receptor (hGR) polymorphisms as a possible cause of altered steroid response. To further evaluate this variability, we hypothesized that hGR polymorphisms along with type of steroid influence the functional response.
  
  
  METHODS
  Total RNA was isolated from healthy human blood samples and surveyed for the hGR gene. The National Center for Biotechnology Information hGRα sequence was used as a reference, and two unique single nucleotide polymorphisms (SNPs) (A214G and T962C) were selected for evaluation. Functional response was measured using a luciferase reporting assay after transfecting hGR isoforms into tsA201 cells and stimulation with graded concentrations of hydrocortisone (HYD), methylprednisolone (MPS), and dexamethasone (DEX).
  
  
  RESULTS
  Each isoform had a unique dose-response curve with the optimal activity depending on concentration and type of steroid. The presence of either SNP A214G or T962C resulted in a decreased response when compared with hGRα when stimulated with HYD (P < 0.01). The same decreased response occurred for the SNPs with DEX stimulation, but at a much lower concentration range than HYD (P < 0.01). However, in the presence of MPS, SNP A214G resulted in greater activity when compared with hGRα (P < 0.01), whereas the presence of T962C resulted in activity equivalent to hGRα.
  
  
  CONCLUSIONS
  SNPs, type of steroid, and concentration range impact the functional response of the hGR. A greater understanding of hGR polymorphisms and steroid response may further elucidate mechanisms explaining the variable response seen with patient treatment.
authors: Shriners Hospitals for Children Northern California, and Department of surgery, University of California, Davis, Sacramento, CA 95817, USA.
authors: Aaron C
authors: AC
authors: Baker
authors: Victoria W
authors: VW
authors: Chew
authors: Tajia L
authors: TL
authors: Green
authors: Kelly
authors: K
authors: Tung
authors: Debora
authors: D
authors: Lim
authors: Kiho
authors: K
authors: Cho
authors: David G
authors: DG
authors: Greenhalgh
mesh_terms: D000328:Adult; D000368:Aged; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000502:physiology; D012772:Shock, Septic / Q000188:drug therapy
chemical_list: D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone; D008775:Methylprednisolone