Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms.

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).
DESIGN: Two dexamethasone (DEX) suppression tests were performed with 1 and 0.25 mg DEX, respectively. PATIENTS: We genotyped a random subgroup of 209 participants of the Rotterdam Study, a population-based study in the elderly. MEASUREMENTS: 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.