A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels
January 2002
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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.
- Male
- Aged
- Aged, 80 and over
- Female
- Humans
- Middle aged
- Research Support, Non-U.S. Gov't
- Risk Factors
- Heterozygote
- Cholesterol/*blood
- *Polymorphism, Restriction Fragment Length
- Blood Glucose
- Receptors, Glucocorticoid/*genetics
- Genetic Predisposition to Disease/epidemiology
- Coronary Disease/epidemiology/*genetics
- Dexamethasone/diagnostic use
- Diabetes Mellitus/epidemiology/*genetics
- Glucocorticoids/diagnostic use
- Gonadal Steroid Hormones/blood
- Insulin/*blood
- Hypothalamo-Hypophyseal System/physiology
- Pituitary-Adrenal System/physiology
- 22/23ek carriers
- 22/23ek
- carrier
- noncarrier
- cortisol
- concentration
- insulin
- fasting
- subject
- cholesterol
- polymorphism
- glucocorticoid
- resistance
- 0.25 mg dex
- difference
- level
- group
- fasting insulin concentrations
- receptor
- 1 mg dex
