Glucocorticoid receptor polymorphisms and metabolic-cardiovascular impairment in adult patients with Addison's disease under glucocorticoid replacement therapy
Roberta Giordano1, Alberto Falorni2, Giorgia Mandrile3, Daniela Gioachino3, Marcella Balbo4, Rita Berardelli4, Ioannis Karamouzis4, Elisa Marinazzo4, Andreea Picu4, Stefania Marzotti2, Serena Romagnoli2, Ezio Ghigo4 & Emanuela Arvat4
Object: In Addisons disease (AD), although glucocorticoid (GC) replacement is essential for health and, indeed, life, several studies showed that conventional GCs doses are involved in metabolic and cardiovascular alterations observed in this disease. As the effects of GCs are mediated by the glucocorticoid receptor (GR), 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 GR gene polymorphisms, including the BclI (rs41423247:C>G), N363S (rs6195:A>G) and ER22/23EK (rs6189:G>A and rs6190:G>A) variants, on waist circumference and metabolic profile (HOMA, OGTT and serum lipids) in 38 AD patients (12 M and 26 F; range of age: 2072 years; BMI: 24.6±0.4 kg/m2) under conventional GC replacement, compared with 38 age-, sex- and BMI-matched controls (CS).
Results: Allelic frequencies of the three polymorphisms between AD and CS were similar. Considering overweight and obese subjects (n=18), mean waist was higher (P<0.05) in AD (94.2±2.3 cm) than in CS (85.8±1.9 cm), being a higher percentage of AD compared to CS connoted by an abdominal fat distribution (83 vs 44%). Neither N363S nor ER22/23EK variants were significantly related to waist in both groups, while AD patients carrying the homozygous BclI polymorphism GG (2 out of 38) had higher (P<0.05) waist circumference (95.5±5.5 cm) than those with wild-type genotype CC (24 out of 38 patients; 90.3±1.9 cm) or heterozygous CG (12 out of 38 patients; 83.9±3.5 cm). A higher percentage of AD compared to CS were IGT (8 vs 0%), hypercholesterolemic (18 vs 8%) and hypertriglyceridemic (18 vs 8%). All AD patients with the GG genotypes had IGT, hypercholesterolemia and hypertryglyceridemia, while 33% of CC and 16% of CG showed metabolic alterations. No statistically significant differences between heterozygous or homozygous BclI carriers and noncarrieres were found for metabolic parameteres in CS.
Conclusion: These preliminary results show that the BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addisons disease and may contribute, together with GC therapy, to the increase of the risk for central adiposity, impaired glucose tolerance and dyslipidemia.