title: A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels.
abstract: We investigated whether a polymorphism in codons 22 and 23 of the glucocorticoid (GC) receptor gene [GAGAGG(GluArg) --> GAAAAG(GluLys)] is associated with altered GC sensitivity, anthropometric parameters, cardiovascular risk factors, and sex steroid hormones. In a subgroup of 202 healthy elderly subjects of the Rotterdam Study, we identified 18 heterozygotes (8.9%) for the 22/23EK allele (ER22/23EK carriers). In the highest age group, the number of ER22/23EK carriers was higher (67-82 years, 12.9%) than in the youngest age group (53-67 years, 4.9%; P < 0.05). Two dexamethasone (DEX) suppression tests with 1 and 0.25 mg DEX were performed, and serum cortisol and insulin concentrations were compared between ER22/23EK carriers and noncarriers. After administration of 1 mg DEX, the ER22/23EK group had higher serum cortisol concentrations (54.8 +/- 18.3 vs. 26.4 +/- 1.4 nmol/l, P < 0.0001), as well as a smaller decrease in cortisol (467.0 +/- 31.7 vs. 484.5 +/- 10.3 nmol/l, P < 0.0001). ER22/23EK carriers had lower fasting insulin concentrations (P < 0.001), homeostasis model assessment- insulin resistance (IR) (index of IR, P < 0.05), and total (P < 0.02) and LDL cholesterol concentrations (P < 0.01). Our data suggest that carriers of the 22/23EK allele are relatively more resistant to the effects of GCs with respect to the sensitivity of the adrenal feedback mechanism than noncarriers, resulting in a better metabolic health profile.
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood*; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D003907:Dexamethasone; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005938:Glucocorticoids; D012739:Gonadal Steroid Hormones / Q000097:blood; D006579:Heterozygote; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000502:physiology; D012150:Polymorphism, Restriction Fragment Length; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D005938:Glucocorticoids; D012739:Gonadal Steroid Hormones; D007328:Insulin; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D002784:Cholesterol