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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
Nature genetics, 12/2004, Letnik: 36, Številka: 12Journal Article
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.
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