We investigated whether a polymorphism at nucleotide position 1220,
resulting in an asparagine-to-serine change at codon 363 in the
glucocorticoid receptor (GR) gene is associated with an altered
sensitivity to glucocorticoids. In a group of 216 elderly persons, 13
heterozygotes for the N363S polymorphism were identified by PCR/single
strand conformation polymorphism analysis. In 2 dexamethasone (DEX)
suppression tests (DSTs), using 1 and 0.25 mg DEX, the circulating
cortisol and insulin concentrations were compared between N363S carriers
and controls. In the 1-mg DST, there were no differences between N363S
carriers and controls, with respect to adrenal suppression, but there was
a significantly higher (P < 0.05) insulin response in N363S carriers. In
the 0.25-mg DST, a significantly larger (P < 0.05) cortisol suppression
and higher (P < 0.05) insulin response were seen in N363S carriers.
Comparison of blood pressure, body mass index (BMI), and bone mineral
density (BMD) between the N363S carriers and controls showed that N363S
carriers had a higher (P < 0.05) BMI but normal blood pressure. There was
an obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the
lumbar spine in N363S carriers. GR characteristics measured in 41 controls
and 9 N363S carriers in peripheral mononuclear leucocytes showed no
differences between N363S carriers and controls, with respect to GR number
and ligand binding affinity. However, there was a trend towards greater
sensitivity to DEX in the carriers' lymphocytes, in a mitogen-induced cell
proliferation assay. In transfection assays, the capacity of the codon 363
variant to activate mouse mammary tumor virus promotor-mediated
transcription in COS-1 cells was unaltered, when compared with the
wild-type GR. We conclude that in 6.0% of our study population, a
polymorphism in codon 363 of the GR gene was found. Individuals carrying
this polymorphism seemed healthy at clinical examination but had a higher
sensitivity to exogenously administered glucocorticoids, with respect to
both cortisol suppression and insulin response. Life-long exposure to the
mutated allele may be accompanied by an increased BMI and a lowered BMD in
the lumbar spine but does not affect blood pressure