Genetic Regulation of Indoleamine-2,3-dioxygenase and Psychiatric Complications o

描述(申请人提供)：吲哚胺-2，3-双加氧酶的遗传调节和干扰素-α治疗的精神并发症精神并发症通常是丙型肝炎干扰素-α治疗的副作用。文献表明，吲哚-胺-2，3-双加氧酶(IDO)是色氨酸(TRY)代谢的犬尿氨酸途径的限速酶，上调是在干扰素-α治疗期间观察到的抑郁、焦虑和精神病的原因：a)IDO的激活分流到增加犬尿氨酸的产生，并远离抗抑郁作用的主要底物-5-羟色胺的合成；以及b)犬尿氨酸代谢物具有引起焦虑和拟精神分裂的作用。IDO在转录水平上由促炎细胞因子诱导。干扰素-α刺激IDO活性和干扰素-γ(IFNG)(IDO最强的转录诱导剂)的产生，以及放大IFNG诱导的IDO表达的肿瘤坏死因子-α(TNF-α)的产生。IFNG(+874)(T/A)和TNF-α(-308)(A/G)基因可能预先决定IFNG和TNF-α的产生水平，从而决定IDO的活动程度和与干扰素-α治疗相关的精神并发症的发生率。我们认为IFNG的高启动子T(+874)和TNF-α的高启动子A(-308)等位基因的结合可能导致IDO的“超诱导”，从而增加了干扰素-α治疗患者的精神并发症的风险。我们的工作假设是，在干扰素-α治疗的精神并发症患者中，拥有IFNG(TT+TA)和肿瘤坏死因子-α(AA+AG)高启动子等位基因组合的个体比没有精神并发症的患者更常见。我们提出了一项横断面的回顾性研究，研究有无精神并发症的丙型肝炎患者对干扰素-α治疗的反应中IFNG(+874)(T/A)和肿瘤坏死因子-α(-308)(A/G/)基因的多态性。所获得的数据可能证明进一步研究基因型、细胞因子水平、IDO活性与精神并发症之间的关系，并为预测和治疗丙型肝炎和其他干扰素治疗疾病(如癌症、肌萎缩侧索硬化症和多发性硬化症)的精神并发症提供新的方法。公共卫生相关性：这项拟议的研究旨在调查细胞因子基因多态性分析是否有助于确定丙型肝炎患者在干扰素-α治疗后发生精神并发症的高风险

DESCRIPTION (provided by applicant): Genetic regulation of indoleamine-2,3-dioxygenase and psychiatric complications of IFN-alpha therapy Psychiatric complications are the often side effects of interferon-alpha (IFN-alpha) therapy of hepatitis C. Literature suggests that the up-regulation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway of tryptophan (TRY) metabolism, is responsible for the depression, anxiety, and psychosis observed during IFN-alpha therapy: a) activation of IDO shunts TRY metabolism to increased production of kynurenines, and away from synthesis of serotonin, the major substrate of antidepressant action; and b) kynurenine metabolites have anxiogenic and psychotomimetic effects. IDO is transcriptionally induced by pro-inflammatory cytokines. IFN-alpha stimulates IDO activity and production of IFN-gamma (IFNG) (the strongest transcriptional inducer of IDO), and of tumor necrosis factor-alpha (TNF-alpha) that amplifies IFNG-induced IDO expression. IFNG (+874) (T/A) and TNF-alpha(-308) (A/G) genotypes might predetermine the level of IFNG and TNF-alpha production, and, consequently, the degree of IDO activity and the frequency of psychiatric complications associated with IFN-alpha treatment. We suggest that combination of the high promoter T of IFNG (+874) with the high promoter A of TNF-alpha (-308) alleles might result in "super-induction" of IDO, and, therefore, in increased risk of psychiatric complications in IFN-alpha treated patients. Our working hypothesis is that individuals possessing a combination of high promoter alleles of IFNG (TT+TA) and TNF-alpha (AA+AG) are more prevalent among IFN-alpha treated patients with psychiatric complications than in patients without psychiatric complications. We propose a cross-sectional retrospective study of IFNG (+874)(T/A) and TNF-alpha(-308) (A/G/) gene polymorphisms in hepatitis C patients with and without psychiatric complications in response to IFN-alpha treatment. The obtained data might justify further studies of association between genotypes, cytokines levels, IDO activity and psychiatric complications, and suggest new ways of prediction and treatment of psychiatric complications of IFN-alpha therapy of hepatitis C and other IFN-alpha treated conditions, e.g., cancer, amyotrophic lateral sclerosis and multiple sclerosis. PUBLIC HEALTH RELEVANCE: The proposed study aims to investigate whether analysis of cytokine gene polymorphisms might help to identify hepatitis C patients with high risk of developing psychiatric complications in response to IFN-alpha therapy