Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder
Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder
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DOI：
10.1038/ng1235
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发表时间：
2003-10-01
期刊：
影响因子：
30.8
通讯作者：
Kato, T
中科院分区：
文献类型：
--
作者：
Kakiuchi, C;Iwamoto, K;Kato, T
双相情感障碍的病理生理学尚不清楚，尽管家族、双胞胎和连锁研究涉及遗传因素[1]。在这里，我们确定了在内质网（ER）应激反应中的关键基因XBP 1，作为双相情感障碍的遗传风险因素。使用DNA微阵列分析的淋巴母细胞来自两对双胞胎不一致的疾病，我们发现在两个受影响的双胞胎ER应激反应相关的基因表达下调。XBP 1启动子区的多态性（-116 C-->G）影响XBP 1的推定结合位点，在日本患者中明显更常见（优势比= 4.6），并且在NIMH双相情感障碍遗传学倡议的三个样本中过度传播给受影响的后代。-116 G等位基因的XBP 1依赖性转录活性低于-116 C等位基因，并且在具有G等位基因的细胞中，ER应激后XBP 1表达的诱导显著降低。丙戊酸盐是三种情绪稳定剂之一，通过诱导XBP 1上游基因ATF 6来挽救受损的反应。这些结果表明，-116 C--> G多态性在XBP 1导致其正反馈系统的损害，并增加双相情感障碍的风险。
The pathophysiology of bipolar disorder is still unclear, although family, twin and linkage studies implicate genetic factors(1). Here we identified XBP1, a pivotal gene in the endoplasmic reticulum ( ER) stress response, as contributing to the genetic risk factor for bipolar disorder. Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of twins discordant with respect to the illness, we found downregulated expression of genes related to ER stress response in both affected twins. A polymorphism (-116C-->G) in the promoter region of XBP1, affecting the putative binding site of XBP1, was significantly more common in Japanese patients ( odds ratio = 4.6) and overtransmitted to affected offspring in trio samples of the NIMH Bipolar Disorder Genetics Initiative. XBP1-dependent transcription activity of the -116G allele was lower than that of the -116C allele, and in the cells with the G allele, induction of XBP1 expression after ER stress was markedly reduced. Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1. These results indicate that the -116C--> G polymorphism in XBP1 causes an impairment of its positive feedback system and increases the risk of bipolar disorder.