BCLI POLYMORPHISM OF THE GLUCOCORTICOID RECEPTOR GENE IS ASSOCIATED WITH INCREASED OBESITY, IMPAIRED GLUCOSE TOLERANCE AND DYSLIPIDEMIA IN PATIENTS WITH ADDISON’S DISEASE

Object: Although glucocorticoids are essential for health, several studies have shown that replacement glucocorticoids in Addison’s disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. Design: We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 Addison’s disease patients (34 F and 16 M, age 20-82 yr) under glucocorticoids replacement. Results: Neither N363S nor ER22/23EK variants were significantly associated with either anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n=4) showed higher (P<0.05) BMI, waist circumference, HOMA and 2-h glucose levels after OGTT, as well as total cholesterol and triglycerides than those with wild-type genotype CC (n=28) or heterozygous CG (n=18). The totality of GG patients was connoted by abdominal adiposity, impaired glucose tolerance/diabetes mellitus or dyslipidemia, while a lower percentage of CC or CG patients showed some anthropometric and metabolic alterations. Conclusion: These results suggest that BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addison’s disease and may contribute, along with other factors, to the increase of central adiposity, impaired glucose metabolism and dyslipidemia.