Division of Endocrinology, Polytechnic University of Marche, Via Conca 71, 60020 Torrette di Ancona, Italy.
Eur J Endocrinol. 2012 Jan;166(1):35-42. doi: 10.1530/EJE-11-0722. Epub 2011 Nov 2.
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.
Sixty-one patients with CS and 71 sex- and age-matched HC were genotyped.
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%, P=0.001) despite the higher levels of both serum morning (21.7±6 vs 27.3±8.6 μg/dl, P=0.009) and midnight cortisol (18.8±5.8 vs 24.0±8.0 μg/dl, P=0.01). The negative association between diabetes and A3669G GR polymorphism remained significant when data were adjusted for potential confounding factors.
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.
糖皮质激素受体（GR）多态性改变糖皮质激素（GC）的敏感性，并与代谢谱的改变有关。我们评估了库欣综合征（CS）患者中四个 GR（NR3C1）多态性 BclI、N363S、ER22/23EK 和 A3669G 的患病率，与健康对照（HC）相比，并根据激素谱研究了它们在 CS 患者代谢异常发展中的作用。
对 61 例 CS 患者和 71 例性别和年龄匹配的 HC 进行基因分型。
CS 患者的 BclI 变异明显高于 HC（62%比 41%，P<0.05），而其他多态性之间无显著差异。N363S 和 ER22/23EK 的发生率极低。在 CS 患者中，尽管 BclI 携带者的清晨血清皮质醇水平明显高于野生型，但未发现临床或代谢差异。相反，与野生型相比，A3669G GR 携带者的 2 型糖尿病患病率显著降低（19%比 68%，P=0.001），尽管清晨（21.7±6 比 27.3±8.6 μg/dl，P=0.009）和午夜（18.8±5.8 比 24.0±8.0 μg/dl，P=0.01）血清皮质醇水平更高。当数据调整为潜在混杂因素时，糖尿病与 GR 基因 A3669G 多态性之间的负相关仍然显著。
GR 基因的 A3669G 多态性在 CS 患者中起保护作用，减轻 GC 过量对葡萄糖代谢的影响，从而降低糖尿病的风险。
