Neopterin and kynurenine as predictors of depression risk and antiviral efficacy

新蝶呤和犬尿氨酸作为抑郁风险和抗病毒功效的预测因子

• 批准号: 8542902
• 负责人: Gregory F Oxenkrug
• 金额: $ 7.63万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542902
• 关键词: Adherence; Adverse effects; Affect; Alleles; Anabolism; Antiviral Agents; Antiviral Response; Biochemical Reaction; Blood; Blood specimen; Chronic Hepatitis C; Data; Enzymes; Evaluation; Genes; Genetic Polymorphism; Genotype; Goals; Healthcare; Hepatitis C virus; Incidence; Infection; Inflammation; Interferon Type II; Interferon-alpha; Interferons; Kynurenine; Liver; Liver Cirrhosis; Major Depressive Disorder; Mental Depression; Metabolism; Methods; Multiple Sclerosis; Neopterin; Outcome; Participant; Patients; Pegylated Interferon Alfa; Plasma; Population; Primary carcinoma of the liver cells; Production; Protease Inhibitor; Pteridines; Reporting; Ribavirin; Risk; Role; Serum; Testing; Tryptophan; Virus; Work; anti-viral efficacy; base; cost effective; genome wide association study; high risk; inflammatory marker; liver transplantation; melanoma; novel marker; premature

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.

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，并涉及频繁和严重的精神副作用。预测抑郁症的风险和IFN-α治疗的抗病毒疗效对于患者的健康和医疗费用都非常重要。IFN-刺激的基因（IFN-SG）同时上调形成新蝶呤（蝶啶生物合成的副产物）和犬尿氨酸（KYN）（色氨酸（TRY）代谢物）的限速酶。我们发现抗病毒应答差的患者（HCV基因型2和3）血浆新蝶呤水平升高; IFN-α诱导的抑郁症与编码IFN-γ产生的IFN-γ基因的高产等位基因相关，IFN-γ是TRY-KYN代谢的最强诱导剂。[1]我们认为，KYN/TRY比值升高预示抑郁症的高风险，新蝶呤水平低预示IFN-α治疗的阳性抗病毒反应。为了验证这一假设，我们建议评估新蝶呤，KYN和TRY水平在已经收集的血液样本的300 HCV参与者从我们完成的研究IFNG（+874）T/A基因多态性在IFN-α诱导的抑郁症。我们的研究将有助于开发快速和具有成本效益的方法，预测IFN-α治疗（单独和与利巴韦林或蛋白酶抑制剂联合）HCV（和其他可用IFN-α治疗的疾病，例如，黑色素瘤、多发性硬化症）;并帮助理解炎症在重度抑郁症中的作用。