Zubenko G S, Hughes H B
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Mol Psychiatry. 2009 Apr;14(4):390-7. doi: 10.1038/mp.2008.23. Epub 2008 Mar 4.
Major depressive disorder (MDD) constitutes a major public health problem worldwide and affects women twice as frequently as men. Previous genetic studies have revealed significant evidence of linkage of the cAMP-responsive element-binding protein 1 (CREB1) gene region (2q33-35) to mood disorders among women from families with recurrent, early-onset MDD (RE-MDD), a severe and familial subtype of MDD. A rare G-to-A transition at position -656 in the CREB1 promoter co-segregates with mood disorders in women from these families, implicating CREB1 as a sex-related susceptibility gene for unipolar mood disorders. In the current study, the functional significance of the CREB1 promoter variant was determined using transfection experiments that employed plasmid constructs containing the wild-type or variant CREB1 promoters coupled to a reporter gene. The results support the hypothesis that the A(-656) allele contributes to the development of MDD in women through selective alteration of CREB1 promoter activity by female gonadal steroids in noradrenergic neuronal cells. Furthermore, exaggeration of these effects during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations.
重度抑郁症（MDD）是全球范围内的一个重大公共卫生问题，女性受其影响的频率是男性的两倍。先前的基因研究已揭示出显著证据，表明在患有复发性早发性MDD（RE-MDD，MDD的一种严重的家族性亚型）的家族中，女性的环磷酸腺苷反应元件结合蛋白1（CREB1）基因区域（2q33 - 35）与情绪障碍存在连锁关系。CREB1启动子中 - 656位的一个罕见的G到A转换与这些家族中女性的情绪障碍共分离，这表明CREB1是单相情绪障碍的一个与性别相关的易感基因。在当前研究中，通过转染实验确定了CREB1启动子变体的功能意义，该实验使用了含有与报告基因偶联的野生型或变体CREB1启动子的质粒构建体。结果支持了这样一种假说，即A（-656）等位基因通过去甲肾上腺素能神经元细胞中女性性腺类固醇对CREB1启动子活性的选择性改变，促成了女性MDD的发生。此外，在模拟应激条件下这些效应的放大可能与报道的基因 - 环境相互作用有关，这些相互作用导致了临床人群中MDD的出现。
