Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment
Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment
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DOI：
10.1038/ng1479
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发表时间：
2004-12-01
期刊：
影响因子：
30.8
通讯作者：
Muller-Myhsok, B
中科院分区：
文献类型：
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作者：
Binder, EB;Salyakina, D;Muller-Myhsok, B
调节应激反应的下丘脑-垂体-肾上腺（HPA）轴与骨质疏松症1以及抑郁症的治疗有关（2）。为了研究调节HPA轴的基因与抗抑郁药反应和抑郁症易感性之间的可能关联，我们对抑郁症患者和对照组中8个基因的单核苷酸多态性进行了基因分型。我们在两个独立的样本中发现，抗抑郁药反应和抑郁发作复发与FKBP 5单核苷酸多态性显著相关，FKBP 5是一种糖皮质激素受体调节HSP-90的辅伴侣。这些单核苷酸多态性也与细胞内FKBP 5蛋白表达增加相关，这引发糖皮质激素受体的适应性变化，从而调节HPA轴。携带相关基因型的个体在抑郁发作期间HPA轴活动较少。我们认为，FKBP 5变体依赖性改变HPA轴调节可能与抗抑郁药物治疗反应更快和抑郁发作复发率增加有关。这些发现支持了调节HPA轴的基因在抑郁症的因果关系和抗抑郁药物的作用机制中的核心作用。
The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality1 as well as the treatment of depression(2). To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.