title: BclI polymorphism of the glucocorticoid receptor gene is associated with increased bone resorption in patients on glucocorticoid replacement therapy.
abstract: BACKGROUND
  Patients with primary adrenal insufficiency (PAI) and patients with congenital adrenal hyperplasia (CAH) receive weight-adapted standard glucocorticoid replacement therapy. Clinically, some patients appear more sensitive to therapeutic administration of glucocorticoids than others. Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR) and might influence bone mineral density (BMD).
  
  
  OBJECTIVE
  To determine if bone turnover markers and BMD are associated with the GR gene polymorphism BclI in patients with PAI and CAH.
  
  
  METHODS
  A prospective, cross-sectional study including 74 PAI and 38 CAH patients. BMD was evaluated by DXA. Serum levels of bone turnover markers, minerals, vitamins and hormones, and urinary crosslinks were measured.
  
  
  RESULTS
  Patients carrying the homozygous BclI polymorphism (GG) had significantly higher serum β-CrossLaps (0.37 ± 0.34 μg/l; P < 0.05) and urinary collagen crosslinks (NTX, 68.1 ± 32.4 nmol/g; P < 0.005) despite receiving the lowest average daily hydrocortisone dose of 9.9 ± 3.7 mg/m(2) (P < 0.05). The GG genotype occurred significantly more frequently in patients with increased NTX (OR=6.7, 95% CI = 1.78-25.38) than in patients with normal NTX. However, BMD was not significantly different between different allelic variants. No significant differences in associations of the genotypes with outcomes (or in clinical characteristics) were found between the sexes.
  
  
  CONCLUSIONS
  Although the sample sizes were relatively small and the results should be interpreted with caution, this study suggests that the homozygous (GG) genotype may be associated with higher bone resorption in adult PAI and CAH patients. GG-carriers needed a lower hydrocortisone dose on average supporting the concept that this GR variant is associated with increased cortisol sensitivity.
authors.affiliation: Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Germany.
authors.forename: Kathrin R
authors.initials: KR
authors.lastname: Koetz
authors.forename: Elisabeth F C
authors.initials: EF
authors.lastname: van Rossum
authors.forename: Manfred
authors.initials: M
authors.lastname: Ventz
authors.forename: Sven
authors.initials: S
authors.lastname: Diederich
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000224:Addison Disease / Q000188:drug therapy* / Q000235:genetics; D000312:Adrenal Hyperplasia, Congenital / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D000368:Aged; D000735:Androstenedione / Q000097:blood; D015519:Bone Density; D001862:Bone Resorption / Q000139:chemically induced*; D003094:Collagen; D024042:Collagen Type I; D003430:Cross-Sectional Studies; D005260:Female; D005938:Glucocorticoids / Q000009:adverse effects; D020249:Hormone Replacement Therapy / Q000009:adverse effects; D006801:Humans; D006854:Hydrocortisone / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010455:Peptides; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011965:Receptors, Glucocorticoid / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D005938:Glucocorticoids; D010455:Peptides; D011965:Receptors, Glucocorticoid; C052929:collagen type I trimeric cross-linked peptide; D000735:Androstenedione; D019326:17-alpha-Hydroxyprogesterone; D003094:Collagen; D006854:Hydrocortisone