Manenschijn Laura, van den Akker Erica L T, Lamberts Steven W J, van Rossum Elisabeth F C
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Ann N Y Acad Sci. 2009 Oct;1179:179-98. doi: 10.1111/j.1749-6632.2009.05013.x.
The glucocorticoid receptor (GR) is crucial for the effects of glucocorticoids (GCs). Several polymorphisms of the GR are associated with altered sensitivity to GCs. For the ER22/23EK polymorphism, a relative GC resistance has been demonstrated. In vivo, this was suggested by a smaller response to a dexamethasone suppression test (DST), whereas in vitro experiments showed a diminished transactivational activity. The associated features of ER22/23EK carriers consist of favorable metabolic and body compositional conditions. In elderly subjects this polymorphism was associated with longevity and decreased risk of dementia. Interestingly, recent studies also showed an increased risk of major depression. In contrast, the N363S polymorphism was reported to be associated with an enhanced sensitivity to GCs, as was demonstrated by a DST. This polymorphism has also been associated with increased body mass index (BMI) and LDL-cholesterol levels, as well as increased risk of cardiovascular disease. However, additional studies yielded conflicting results, showing no associations with being overweight. The BclI polymorphism is also associated with increased GC sensitivity. In addition, associations with increased abdominal fat mass, Crohn's disease and, remarkably, major depression have been reported. Another GR polymorphism, located in exon 9beta, is associated with increased expression and stabilization of the dominant negative splice variant GR-beta. Carriers of this polymorphism displayed a relative GC resistance in vitro as evidenced by diminished transrepressional activity, which is important for the immune system and inflammation. Associations have been found with increased inflammatory parameters, cardiovascular disease, and rheumatoid arthritis. In this article, studies concerning these clinically relevant GR variants are discussed.
糖皮质激素受体（GR）对于糖皮质激素（GCs）的作用至关重要。GR的几种多态性与对GCs的敏感性改变有关。对于ER22/23EK多态性，已证实存在相对的GC抵抗。在体内，地塞米松抑制试验（DST）反应较小表明了这一点，而体外实验显示其反式激活活性降低。ER22/23EK携带者的相关特征包括良好的代谢和身体成分状况。在老年受试者中，这种多态性与长寿和痴呆风险降低有关。有趣的是，最近的研究还显示重度抑郁症风险增加。相比之下，据报道N363S多态性与对GCs的敏感性增强有关，这在地塞米松抑制试验中得到了证实。这种多态性还与体重指数（BMI）和低密度脂蛋白胆固醇水平升高以及心血管疾病风险增加有关。然而，其他研究得出了相互矛盾的结果，表明与超重无关。BclI多态性也与GC敏感性增加有关。此外，还报道了与腹部脂肪量增加、克罗恩病以及引人注目的重度抑郁症有关。另一种位于外显子9β的GR多态性与显性负性剪接变体GR-β的表达增加和稳定性有关。这种多态性的携带者在体外表现出相对的GC抵抗，反式抑制活性降低证明了这一点，而反式抑制活性对免疫系统和炎症很重要。已发现其与炎症参数增加、心血管疾病和类风湿性关节炎有关。在本文中，将讨论有关这些临床相关GR变体的研究。
