Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing-related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test.

中文翻译：

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RNA编辑血液生物标志物，用于预测HCV患者的情绪变化。

急诊抑郁症是接受IFN-α和利巴韦林抗病毒联合治疗的慢性丙型肝炎病毒（HCV）感染患者的常见并发症。最近显示，A-to-I RNA编辑率的变化与各种病理学有关，例如炎性疾病，抑郁症和自杀。有趣的是，IFN-α诱导了RNA编辑酶ADAR1-1（ADAR1a-p150）的基因表达，并改变了总体RNA编辑活性。在这项研究中，我们利用了用IFN-α和利巴韦林治疗的患者中药理学上引起的抑郁症的高患病率，来检验患者白细胞中与RNA编辑相关的生物标志物的兴趣。在这项为期16周的纵向研究中，在抗病毒治疗之前和期间，使用标准评估方法对一小部分患者进行了临床评估，并收集了血液样本以分析RNA编辑修饰。磷酸二酯酶8A（PDE8A）基因（先前在红斑狼疮的情况下已确定的RNA编辑热点）的AI RNA编辑活性通过使用超深度下一代测序方法进行了定量。我们还通过qPCR监测了ADAR酶和PDE8A基因的基因表达水平。正如预期的那样，精神病学评估可以追踪治疗后的抑郁症，这种抑郁症发生在30％的HCV患者中。我们显示，干扰素治疗后所有患者的PDE8A RNA编辑均增加，但30％的患者有所不同。在使用SHSY-5Y神经母细胞瘤细胞的细胞模型中可以模仿这种效果。通过将AI RNA编辑和基因表达的数据相结合，我们生成了一种算法，该算法可以区分发生治疗性抑郁症的患者和没有发生抑郁症的患者。当前的药物诱发的抑郁症模型将AI RNA编辑生物标记物识别为有用的工具，可用于在客观，可量化的生物血液测试中识别处于患抑郁症风险的个体。