Clinical Features Associated with Glucocorticoid Receptor Polymorphisms An Overview
Clinical Features Associated with Glucocorticoid Receptor Polymorphisms An Overview
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DOI：
10.1111/j.1749-6632.2009.05013.x
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发表时间：
2009-01-01
期刊：
影响因子：
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通讯作者：
van Rossum, Elisabeth F. C.
中科院分区：
文献类型：
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作者：
Manenschijn, Laura;van den Akker, Erica L. T.;van Rossum, Elisabeth F. C.
糖皮质激素受体（GR）是糖皮质激素（GC）发挥作用的关键。GR的几种多态性与对GC的敏感性改变有关。对于ER 22/23 EK多态性，已经证明了相对GC抗性。在体内，这是由一个较小的反应地塞米松抑制试验（DST），而在体外实验表明，减少反式激活活性。ER 22/23 EK携带者的相关特征包括有利的代谢和身体组成条件。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，最近的研究也表明，患重度抑郁症的风险增加。与此相反，N363 S多态性被报道与GC敏感性增强相关，如DST所示。这种多态性也与体重指数（BMI）和LDL胆固醇水平增加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，显示与超重无关。Bell多态性也与GC敏感性增加相关。此外，与腹部脂肪量增加，克罗恩病，显着，严重抑郁症的协会已报告。位于外显子9 β的另一种GR多态性与显性负剪接变体GR-β的表达增加和稳定性相关。这种多态性的携带者在体外表现出相对的GC抗性，这通过降低的反式抑制活性来证明，这对免疫系统和炎症是重要的。已发现与炎症参数增加、心血管疾病和类风湿性关节炎相关。在这篇文章中，这些临床相关的GR变异的研究进行了讨论。
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 Bell 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 9 beta, 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.