Zubenko George S, Hughes Hugh B
Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):579-85. doi: 10.1002/ajmg.b.30708.
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 CREB1 region 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 cosegregates 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 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 by selectively altering the activity of the CREB1 promoter in glial cells exposed to 17 beta-estradiol. Furthermore, the exaggeration of this effect during a simulated stress condition may be relevant to reported gene-environment interactions that contribute to the emergence of MDD in clinical populations. The results of in silico analysis revealed four putative binding sites for transcription factors that are affected by the G to A transition at position -656, of which CP2 best fit the experimental observations.
重度抑郁症（MDD）是全球主要的公共卫生问题，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，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CREB1区域与情绪障碍存在显著的连锁证据。CREB1启动子中-656位的一个罕见的G到A的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。在当前的研究中，使用转染实验确定了CREB1启动子变体的功能意义，该实验采用了含有与报告基因偶联的野生型或变体CREB1启动子的构建体。结果支持这样的假设，即A（-656）等位基因通过选择性地改变暴露于17β-雌二醇的神经胶质细胞中CREB1启动子的活性，促进女性MDD的发生。此外，在模拟应激条件下这种效应的放大可能与报道的基因-环境相互作用有关，这些相互作用导致临床人群中MDD的出现。计算机分析结果揭示了4个转录因子的假定结合位点，它们受-656位G到A转换的影响，其中CP2最符合实验观察结果。
