Neopterin and kynurenine as predictors of depression risk and antiviral efficacy

描述（由申请人提供）：干扰素(IFN)- α治疗丙型肝炎病毒（HCV）的疗效有限，并且涉及频繁和严重的精神副作用。预测抑郁风险和ifn - α治疗的抗病毒效果对患者的健康和医疗费用具有重要意义。IFN刺激基因（IFN- sgs）同时上调新蝶呤（蝶呤生物合成的副产物）和色氨酸（TRY）代谢物犬尿氨酸（KYN）形成的限速酶。我们发现抗病毒反应较差的HCV基因型2和3型患者血浆新蝶呤水平升高；ifn α诱导的抑郁症与ifn - γ基因的高产生等位基因有关，该基因编码ifn - γ的产生，ifn - γ是TRY - KYN代谢的最强诱导剂我们认为，KYN/TRY比值升高预示着抑郁的高风险，而低neopterin水平预示着对ifn - α治疗的阳性抗病毒反应。为了验证这一假设，我们建议评估已收集的300名HCV参与者血液样本中的neopterin， KYN和TRY水平，这些样本来自我们完成的ifn - α诱导的抑郁症中IFNG (+874) T/A基因多态性研究。我们的研究将有助于开发快速且具有成本效益的方法，预测ifn - α治疗HCV（以及其他可用ifn - α治疗的疾病，如黑色素瘤、多发性硬化症）的主要结果；并有助于理解炎症在重度抑郁症中的作用。

DESCRIPTION (provided by applicant): Interferon (IFN)-alpha treatment of hepatitis C virus (HCV) has limited efficacy and involves frequent and severe psychiatric side-effects. Prediction of risk for depression and antiviral efficacy of IFN-alpha treatment is of great importance for bot patient wellbeing and health care expense. IFN- stimulated genes (IFN-SGs) concurrently up-regulates rate-limiting enzymes of formation of neopterin, a by-product of pteridines biosynthesis, and kynurenine (KYN), a tryptophan (TRY) metabolite. We found elevated plasma levels of neopterin in patients (HCV genotypes 2 and 3) with poor anti-viral response; and association of IFN-alpha-induced depression with a high producer allele of IFN-gamma gene that encodes production of IFN-gamma, the strongest inducer of TRY - KYN metabolism.[1] We suggest that elevated KYN/TRY ratio predicts high risk of depression and low neopterin levels predict positive anti-viral response to IFN-alpha treatment. To test this hypothesis we propose to assess neopterin, KYN and TRY levels in already collected blood samples of 300 HCV participants from our completed study of IFNG (+874) T/A gene polymorphisms in IFN-alpha-induced depression. Our study will help to develop rapid and cost-effective methods predicting the major outcomes of IFN-alpha therapy (alone and in combination with ribavirin or protease inhibitors) of HCV (and other conditions treatable with IFN-alpha, e.g., melanoma, multiple sclerosis); and help to understand the role of inflammation in major depressive disorder. PUBLIC HEALTH RELEVANCE: This proposal aims to develop a rapid and reliable method for prediction of risk for depression and anti-viral efficacy of interferon-alpha treatment of hepatiti C virus patients. Method will consist of the assessment of plasma levels of markers of inflammation: neopterin, and kynurenine/tryptophan ratio.