Association of glucocorticoid receptor polymorphism A3669G with decreased risk of developing diabetes in patients with Cushing's syndrome

Abstract

Objective: Glucocorticoid receptor (GR) polymorphisms alter glucocorticoid (GC) sensitivity and have been associated with altered metabolic profiles. We evaluate the prevalence of the four GR (NR3C1) polymorphisms BclI, N363S, ER22/23EK, and A3669G in patients with Cushing's syndrome (CS) compared with healthy controls (HC) and we investigate their role in the development of metabolic abnormalities in patients with CS according to their hormonal profile. Patients and methods: Sixty-one patients with CS and 71 sex-and age-matched HC were genotyped. Results: BclI variant was markedly higher in patients with CS compared with HC (62 vs 41%, P!0.05) while no significant differences were found among other polymorphisms. A very low frequency of N363S and the ER22/23EK was observed. In CS patients, despite the significantly increased levels of morning serum cortisol in BclI carriers compared with wild type no clinical or metabolic differences were found. In contrast, A3669G GR carriers showed a significantly reduced prevalence of type 2 diabetes mellitus compared with wild type (19 vs 68%, PZ0.001) despite the higher levels of both serum morning (21.7G6 vs 27.3G8.6 mg/dl, PZ0.009) and midnight cortisol (18.8G5.8 vs 24.0G8.0 mg/dl, PZ0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors. Conclusions: The A3669G polymorphism of the GR gene plays a protective role in patients with CS, attenuating the effects of GC excess on glucose metabolism as shown by their reduced risk of diabetes.

Body composition and bone mineral density in women with Cushing's syndrome in remission and the association with common genetic variants influencing glucocorticoid sensitivity

“…This and that the deviation from HWE were not observed in the control group argues against a technical error during the analytical procedure. Interestingly, a similar finding has been observed previously (18). One can therefore speculate whether this genetic variant is associated with the development of the CS itself.…”

“…Five single-nucleotide polymorphisms (SNPs) in four genes were analysed; Bcl1 (rs41423247) and A3669G (rs6198) in the NR3C1 gene, I180V (rs5522) in the NR3C2 gene, rs11119328 in the HSD11B1 gene and rs1045642 in the ABCB1 gene. The selection of the candidate genes was based on their previously described effects on GC sensitivity (16,17,18,19,20,21,22). Due to the limited size of our cohort, we chose only SNPs with a minor allele frequency (MAF) O10% in the HapMap CEU Panel.…”

“…The median (interquartile rage) time in remission was 13 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) years. Nineteen (38%) patients were receiving GC replacement therapy: ten after bilateral adrenalectomy, seven due to pituitary insufficiency after transsphenoidal pituitary surgery and/or radiotherapy and two after unilateral adrenalectomy.…”

“…Several polymorphisms in the GC receptor gene (NR3C1) are described that may either increase (BcI1 and N363S) or decrease (ER22/23EK and A3669G) GC sensitivity (16). In patients with active CS, BclI is associated with reduced BMD (17) and A3669G, with a decreased risk of developing diabetes mellitus (18). In addition, polymorphisms in the genes coding for the mineralocorticoid receptor (NR3C2) (19), 11b-hydroxysteroid dehydrogenase type 1 (HSD11B1) (20,21) and ATP-binding cassette B1 (ABCB1) (22) may also be important for GC sensitivity.…”

The degree of urinary hypercortisolism is not correlated with the severity of cushing’s syndrome

“…However, all these pathogenetic factors are not completely known. Maybe, the degree and duration of hypercortisolism have a crucial role, even though other factors might have an influence in determining CS complications [18,19].…”