Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with higher prevalence in women, that leads to neurological disability. The disease course and clinical phenotype are highly variable, and therefore, biomarkers for the diagnosis, classification, monitoring of the disease and treatment assessment are needed. Studies have shown a dysregulation in the coding and non-coding RNAs and proposed some as biomarkers. However, still none of them have reached the clinical practice. Recently, circular RNAs (circRNAs) have emerged as new players in the transcriptome that hold a great potential as biomarkers in several diseases. Leukocytes from 30 MS patients and 20 healthy controls (HCs) were RNA-sequenced to study the linear and circular transcriptome. Differential expression analysis was performed by DESeq, and circRNA candidates were studied in a second cohort (70 MS and 46 HC) by RT-qPCR and in paired samples drawn during the relapse and remission phases (20 patients). Among the differentially expressed circRNAs, 96.1% are upregulated in patients compared with controls, but similar circRNA profiles are found between MS types. The same upregulation trend was observed in females but not in males or in the linear transcriptome. The upregulation of 6 circRNAs was validated, and a change in their expression was found between relapse and remission. The 6 circRNAs showed a good performance to discriminate patients from HC with a combined area under the curve of 0.852. There is global, specific and sex-dependent increase of circRNA expression in MS, and 6 circRNAs are proposed as potential biomarkers.

中文翻译：

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白细胞的 RNA-Seq 分析揭示了多发性硬化症和 6 个候选生物标志物中的性别依赖性全局环状 RNA 上调

多发性硬化症 (MS) 是一种慢性中枢神经系统自身免疫性疾病，女性患病率较高，可导致神经功能障碍。病程和临床表型变化很大，因此需要用于疾病诊断、分类、监测和治疗评估的生物标志物。研究表明编码和非编码 RNA 的失调，并提出了一些作为生物标志物。然而，它们都没有达到临床实践。最近，circRNAs (circRNAs) 已成为转录组中的新参与者，在多种疾病中具有作为生物标志物的巨大潜力。对来自 30 名 MS 患者和 20 名健康对照 (HC) 的白细胞进行 RNA 测序以研究线性和环状转录组。DESeq进行差异表达分析，和 circRNA 候选者通过 RT-qPCR 在第二个队列（70 MS 和 46 HC）中以及在复发和缓解阶段（20 名患者）期间抽取的配对样本中进行研究。在差异表达的 circRNA 中，与对照组相比，患者中 96.1% 的表达上调，但在 MS 类型之间发现了相似的 circRNA 谱。在女性中观察到相同的上调趋势，但在男性或线性转录组中未观察到。验证了 6 个 circRNA 的上调，并且发现在复发和缓解之间它们的表达发生了变化。6个circRNA表现出良好的区分HC患者的性能，曲线下面积为0.852。MS 中 circRNA 表达存在全局性、特异性和性别依赖性增加，6 种 circRNA 被提议作为潜在的生物标志物。