Neopterin and kynurenine as predictors of depression risk and antiviral efficacy

描述(申请人提供)：干扰素(干扰素)-α治疗丙型肝炎病毒(丙型肝炎病毒)的疗效有限，并涉及频繁和严重的精神副作用。预测BOT患者抑郁的风险和干扰素-α治疗的抗病毒效果对BOT患者的健康和医疗费用具有重要意义。干扰素刺激基因(IFN-SGS)同时上调形成新蝶呤和犬尿氨酸的限速酶，新蝶呤是蝶类药物生物合成的副产物，犬尿氨酸是色氨酸(Try)的代谢物。我们发现抗病毒反应差的患者(丙型肝炎病毒2型和3型)血浆新喋呤水平升高；干扰素-α引起的抑郁与干扰素-伽玛基因的高产生等位基因有关，干扰素-伽玛基因编码产生干扰素-伽马的最强诱导剂。[1]我们认为，升高的kyn/try比率预示着抑郁的高风险，而低的新喋呤水平预示着对干扰素-α治疗的阳性抗病毒反应。为了验证这一假设，我们建议评估已经收集的300名丙型肝炎患者的血液样本中的新喋呤、KYN和Try水平，这些样本来自我们完成的干扰素-α诱导的抑郁中IFNG(874)T/A基因多态的研究。我们的研究将有助于开发快速、经济有效的方法来预测丙型肝炎病毒干扰素-α治疗(以及其他可用干扰素-α治疗的疾病，如黑色素瘤、多发性硬化症)的主要结果(单独和联合利巴韦林或蛋白酶抑制剂)；并有助于了解炎症在严重抑郁障碍中的作用。 公共卫生相关性：这项建议旨在开发一种快速、可靠的方法来预测丙型肝炎病毒患者抑郁的风险和干扰素-α治疗的抗病毒效果。方法将包括评估血浆炎症标志物的水平：新喋呤和犬尿氨酸/色氨酸比率。

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.