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.