title: Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms.
abstract: OBJECTIVE
  Sensitivity to glucocorticoids within the normal population is highly variable and partly determined by polymorphisms in the glucocorticoid receptor (GR) gene (NR3C1). We investigated the exact sequence alteration of a TthIIII polymorphism in the GR gene, whether it is associated with glucocorticoid sensitivity, and its relationship to 3 polymorphisms of the GR gene (N363S, BclI, ER22/23EK).
  
  
  METHODS
  Two dexamethasone (DEX) suppression tests were performed with 1 and 0.25 mg DEX, respectively.
  
  
  METHODS
  We genotyped a random subgroup of 209 participants of the Rotterdam Study, a population-based study in the elderly.
  
  
  METHODS
  Anthropometric parameters, cortisol, insulin and glucose levels, and lipid concentrations were measured.
  
  
  RESULTS
  We identified the TthIIII polymorphism as a C to T mutation, 3807 bp upstream from the mRNA start site. We found 39.7% CC-carriers, 44.5% CT-carriers, and 15.8 % TT-carriers. No differences were found between TthIIII genotypes in sensitivity to DEX, baseline cortisol, insulin, glucose or cholesterol levels, or in anthropometric variables. However, all ER22/23EK-carriers also carried the TthIIII T-allele, and carriers of both these polymorphisms had a significantly smaller cortisol suppression after 1 mg DEX, lower fasting insulin levels, and lower total and low-density lipoprotein (LDL) cholesterol levels than TthIIII T carriers without the ER22/23EK variant and noncarriers. No interaction was found between the TthIIII variant and N363S or BclI polymorphisms.
  
  
  CONCLUSIONS
  The TthIIII polymorphism is not functional by itself. However, the ER22/23EK polymorphism is without exception linked to the TthIIII T polymorphism and this haplotype is associated with a relative resistance to glucocorticoids, and a healthy metabolic profile.
authors.affiliation: Department of Internal Medicine, Erasumus Medical Center, Rotterdam, The Netherlands. e.vanrossum@erasmusmc.nl
authors.forename: Elisabeth F C
authors.initials: EF
authors.lastname: van Rossum
authors.forename: Petronella H M
authors.initials: PH
authors.lastname: Roks
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: Albert O
authors.initials: AO
authors.lastname: Brinkmann
authors.forename: Huib A P
authors.initials: HA
authors.lastname: Pols
authors.forename: Jan W
authors.initials: JW
authors.lastname: Koper
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001786:Blood Glucose / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D001786:Blood Glucose; D008078:Cholesterol, LDL; D005938:Glucocorticoids; D007328:Insulin; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D002784:Cholesterol; D006854:Hydrocortisone