Binder Elisabeth B, Salyakina Daria, Lichtner Peter, Wochnik Gabriele M, Ising Marcus, Pütz Benno, Papiol Sergi, Seaman Shaun, Lucae Susanne, Kohli Martin A, Nickel Thomas, Künzel Heike E, Fuchs Brigitte, Majer Matthias, Pfennig Andrea, Kern Nikola, Brunner Jürgen, Modell Sieglinde, Baghai Thomas, Deiml Tobias, Zill Peter, Bondy Brigitta, Rupprecht Rainer, Messer Thomas, Köhnlein Oliver, Dabitz Heike, Brückl Tanja, Müller Nina, Pfister Hildegard, Lieb Roselind, Mueller Jakob C, Lõhmussaar Elin, Strom Tim M, Bettecken Thomas, Meitinger Thomas, Uhr Manfred, Rein Theo, Holsboer Florian, Muller-Myhsok Bertram
Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
Nat Genet. 2004 Dec;36(12):1319-25. doi: 10.1038/ng1479. Epub 2004 Nov 21.
The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. 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.
调节应激激素的下丘脑 - 垂体 - 肾上腺（HPA）轴与抑郁症的病因及治疗均有关联。为了研究调节HPA轴的基因与抗抑郁药反应及抑郁症易感性之间的可能关联，我们对抑郁症患者及匹配的对照组中这八个基因的单核苷酸多态性进行了基因分型。在两个独立样本中，我们发现抗抑郁药反应及抑郁发作复发与FKBP5（一种hsp - 90的糖皮质激素受体调节伴侣蛋白）中的单核苷酸多态性存在显著关联。这些单核苷酸多态性还与细胞内FKBP5蛋白表达增加相关，这会引发糖皮质激素受体的适应性变化，进而调节HPA轴。携带相关基因型的个体在抑郁发作期间HPA轴的过度活跃程度较低。我们提出，HPA轴调节中FKBP5变异依赖性改变可能与该亚组抑郁症患者对抗抑郁药物治疗的更快反应以及抑郁发作复发增加有关。这些发现支持了调节HPA轴的基因在抑郁症病因及抗抑郁药物作用机制中起核心作用。
