A POLYMORPHISM IN THE GLUCOCORTICOID RECEPTOR GENE MAY BE ASSOCIATED WITH AN INCREASED SENSITIVITY TO GLUCOCORTICOIDS IN-VIVO

We investigated whether a polymorphism at nucleotide position 1220, re sulting in an asparagine-to-serine change at codon 363 in the glucocor ticoid 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 confor mation polymorphism analysis. In 2 dexamethasone (DEX) suppression tes ts (DSTs), using 1 and 0.25 mg DEX, the circulating cortisol and insul in concentrations were compared between N363S carriers and controls. I n the l-mg DST, there were no differences between N363S carriers and c ontrols, with respect to adrenal suppression, but there was a signific antly higher (P < 0.05) insulin response in N363S carriers. In the 0.2 5-mg DST, a significantly larger (P < 0.05) cortisol suppression and h igher (P < 0.05) insulin response were seen in N363S carriers. Compari son of blood pressure, body mass index (BMI), and bone mineral density (BMD) between the N363S carriers and controls showed that N363S carri ers had a higher (P < 0.05) BMI but normal blood pressure. There was a n obvious trend towards lower age-, BMI-, and sex-adjusted BMD in the lumbar spine in N363S carriers. GR characteristics measured in 41 cont rols 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 toward s greater sensitivity to DEX in the carriers' lymfocytes, in a mitogen -induced cell proliferation assay. In transfection assays, the capacit y of the codon 363 variant to activate mouse mammary tumor virus promo tor-mediated transcription in COS-I cells was unaltered, when compared with the wild-type GR. We conclude that in 6.0% of our study populati on, 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-l ong 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 pr essure.