Chronically elevated cortisol levels can increase body fat, as seen clearly in Cushing's syndrome. Subjects with abdominal obesity share many of the hormonal, metabolic, and circulatory characteristics of people with Cushing's syndrome. A dysfunctional glucocorticoid receptor may add to the adverse health effects of excessive cortisol concentrations.
An Asn363Ser polymorphism in exon 2 of the glucocorticoid receptor gene (GRL) might be associated with overweight and an increased sensitivity to exogenous glucocorticoids.1 We therefore examined whether this variant was associated with altered sensitivity to glucocorticoids as well as obesity with its related metabolic and haemodynamic abnormalities in a cohort of Swedish men.2
Participants, methods, and results
Subjects (a total of 284 men) were randomly selected from a larger cohort of men born in Gothenburg, Sweden, in 1944. The design of the study has been described elsewhere.3 Measurements reported here were carried out in Gothenburg during 1995. All men gave written informed consent before participating in the study, which was approved by the local ethics committee.
Anthropometric measurements included body mass index, waist to hip ratio, and abdominal sagittal diameter. Salivary cortisol was measured repeatedly during an ordinary working day that had been selected at random. In addition, an overnight low dose (0.5 mg) dexamethasone suppression test was performed at home and the difference in the salivary cortisol concentration before and after dexamethasone intake was calculated.3 Endocrine measurements, other than cortisol, included testosterone, insulin-like growth factor I, and leptin, as described previously.3 The following were measured in the overnight fasting state: insulin, glucose, triglycerides; total, high, and low density lipoprotein cholesterol; systolic and diastolic blood pressures; and heart rate.
Genotyping was performed on leucocyte DNA. Polymerase chain reaction amplification of the exon 2 of GRL was done using primers described previously,4 and the products were digested with Tsp509I, which disclosed two genotypes—Asn363Asn and Asn363Ser.
The table shows the results for the two genotypes of GRL (table). There were 25 heterozygotes. The two groups of genotypes had similar anthropometry and endocrine, metabolic, and haemodynamic variables.
Comment
Our study shows that a point variation from ATT to GTT in exon 2 of GRL, resulting in a change from asparagine to serine at codon 363, is not associated with an altered sensitivity to glucocorticoids or with obesity and its related metabolic and haemodynamic perturbations. The frequency of the rare allele was 0.05 in our cohort, which is comparable to previous reports (0.07 and 0.03).1,2
The Ser363 variant is not associated with variables indicative of resistance to glucocorticoids.4 In addition, at baseline examination in a previous report, the body mass index was not significantly higher in carriers of Ser363.2 These findings are similar to those reported here.
The disparity between our study and previous work might reflect differences in genetic background or a different degree of linkage in the populations because the Asn363Ser polymorphism might serve as a marker for a yet unidentified functional variant.1 We have recently shown that a BclI polymorphism in intron 1 of GRL was associated with decreased sensitivity to raised postprandial secretion of cortisol and several cardiovascular risk factors.5 Consequently, we investigated the potential effects of interaction between Tsp509I and the BclI marker and showed that the BclI intronic mutation does not interact with the Ser363 variant for any of the phenotypes under study.
We conclude that GRL has several different polymorphisms and mutations, but that few of these are consistently associated with obesity and subtle physiological alterations in the hypothalamic-pituitary-adrenal axis regulating cortisol secretion. The Asn363Ser polymorphism does not seem to be one of the variants associated with such changes.
Table.
Differences in anthropometric, endocrine, metabolic, and haemodynamic measurements by genotype of the GRL polymorphism. The confidence interval is for the mean difference; values are given as mean (SD)
| Genotype
|
95% CI | ||
|---|---|---|---|
| Asn363Asn (n=243) | Asn363Ser (n=25) | ||
| Body mass index (kg/m2) | 26.2 (3.9) | 26.0 (3.8) | −1.8 to 1.4 |
| Waist circumference (cm) | 95.4 (11.4) | 93.8 (11.8) | −6.4 to 3.1 |
| Waist to hip ratio | 0.94 (0.07) | 0.93 (0.08) | −0.04 to 0.02 |
| Abdominal sagittal diameter (cm) | 22.7 (3.7) | 22.1 (3.4) | −2.1 to 0.9 |
| Total salivary cortisol level (nmol/l) | 7.5 (3.9) | 7.1 (1.7) | −2.1 to 1.3 |
| Dexamethasone suppression test (nmol/l) | 12.0 (5.4) | 11.9 (4.5) | −2.5 to 2.3 |
| Testosterone (nmol/l) | 19.7 (5.3) | 19.6 (6.7) | −2.9 to 2.8 |
| Insulin-like growth factor I (μg/l) | 205.5 (65.0) | 206.1 (66.1) | −26.3 to 27.5 |
| Leptin (μg/l) | 6.2 (4.4) | 5.2 (3.5) | −2.8 to 0.8 |
| Fasting insulin (mU/l) | 12.5 (9.7) | 13.7 (19.4) | −3.4 to 5.7 |
| Fasting glucose (mmol/l) | 4.6 (1.0) | 4.3 (0.7) | −0.7 to 0.1 |
| Triglycerides (mmol/l) | 1.8 (1.0) | 2.1 (1.4) | −0.2 to 0.7 |
| Total cholesterol (mmol/l) | 6.1 (1.0) | 6.4 (1.3) | −0.2 to 0.7 |
| High density lipoprotein cholesterol (mmol/l) | 1.3 (0.3) | 1.2 (0.3) | −0.2 to 0.1 |
| Low density lipoprotein cholesterol (mmol/l) | 4.1 (1.0) | 4.2 (1.1) | −0.3 to 0.6 |
| Systolic blood pressure (mm Hg) | 129.9 (17.7) | 125.1 (15.0) | −12.0 to 2.4 |
| Diastolic blood pressure (mm Hg) | 83.7 (10.6) | 81.7 (9.3) | −6.3 to 2.3 |
| Heart rate (beats/min) | 68.9 (10.6) | 68.5 (9.3) | −4.8 to 4.0 |
Acknowledgments
We thank Monique Chagnon, laboratory coordinator at Pennington Biomedical Research Center, for preparing and supervising the genotyping.
Editorial by Sørensen and Echwald
Footnotes
Funding: Grants from the Swedish Medical Research Council (K97-19X-00251-35A) and the Pennington Biomedical Research Center. RR acknowledges the Henning and Johan Throne-Holst Foundation for a postdoctoral fellowship at the Pennington Biomedical Research Center.
Competing interests: None declared.
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