Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease.
Transcriptional signature associated with early rheumatoid arthritis and healthy individuals at high risk to develop the disease.
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DOI：
10.1371/journal.pone.0194205
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Enciso-Moreno JA
中科院分区：
文献类型：
--
作者：
Macías-Segura N;Castañeda-Delgado JE;Bastian Y;Santiago-Algarra D;Castillo-Ortiz JD;Alemán-Navarro AL;Jaime-Sánchez E;Gomez-Moreno M;Saucedo-Toral CA;Lara-Ramírez EE;Zapata-Zuñiga M;Enciso-Moreno L;González-Amaro R;Ramos-Remus C;Enciso-Moreno JA
关于自身免疫性疾病早期和临床前阶段耐受性丧失的机制，人们知之甚少。这项工作的目的是确定与未治疗的早期类风湿性关节炎(RA)和高危受试者相关的转录特征和信号通路。提出了几种早期RA的候选生物标志物。全血总RNA取自1年前未经治疗的早期RA患者和RA(FDR)患者的健康一级亲属，根据其血清中抗环瓜氨酸肽的抗体水平分为ACCP+和ACCP-。合成互补RNA(CRNA)并与高密度微阵列杂交。在Genespring软件中对数据进行分析，并将功能类别分配给在RA和FDR ACCP阳性的受试者中识别的特定转录组。确定了与RA相关的基因的特定信号通路。用定量聚合酶链式反应(QPCR)检测基因表达。用受试者工作特征(ROC)分析评估这些基因作为生物标志物。在早期RA患者中发现了551个诱导基因和4402个抑制基因的特征转录组。数据的生物信息学分析在RA患者中发现了一个特定的转录组。此外，在RA患者和ACCP+患者之间发现了一些重叠的转录图谱，表明从临床前阶段到进展到早期RA状态，有一个上调的独特转录组。共有203条途径具有在RA和ACCP+之间共享的上调基因。其中一些基因有可能被用作早期RA的进展生物标志物，其面积在ROC>；0.92曲线下。这些基因来自与炎症、Wnt信号和I型干扰素途径相关的几个功能类别。在RA患者的全血中存在一个特定的转录组，这表明在RA的早期发展中，一个特定的炎性转录信号被激活。在早期RA患者中，与ACCP+受试者共享但与ACCP受试者不共享的一组过表达基因可以代表参与临床前RA阶段向临床RA阶段转变的转录信号。这些特定的上调和下调基因中的一些与炎症过程有关，可以被认为是类风湿关节炎高危人群疾病进展的生物标记候选。
Little is known regarding the mechanisms underlying the loss of tolerance in the early and preclinical stages of autoimmune diseases. The aim of this work was to identify the transcriptional profile and signaling pathways associated to non-treated early rheumatoid arthritis (RA) and subjects at high risk. Several biomarker candidates for early RA are proposed. Whole blood total RNA was obtained from non-treated early RA patients with <1 year of evolution as well as from healthy first-degree relatives of patients with RA (FDR) classified as ACCP+ and ACCP- according to their antibodies serum levels against cyclic citrullinated peptides. Complementary RNA (cRNA) was synthetized and hybridized to high-density microarrays. Data was analyzed in Genespring Software and functional categories were assigned to a specific transcriptome identified in subjects with RA and FDR ACCP positive. Specific signaling pathways for genes associated to RA were identified. Gene expression was evaluated by qPCR. Receiver operating characteristic (ROC) analysis was used to evaluate these genes as biomarkers. A characteristic transcriptome of 551 induced genes and 4,402 repressed genes were identified in early RA patients. Bioinformatics analysis of the data identified a specific transcriptome in RA patients. Moreover, some overlapped transcriptional profiles between patients with RA and ACCP+ were identified, suggesting an up-regulated distinctive transcriptome from the preclinical stages up to progression to an early RA state. A total of 203 pathways have up-regulated genes that are shared between RA and ACCP+. Some of these genes show potential to be used as progression biomarkers for early RA with area under the curve of ROC > 0.92. These genes come from several functional categories associated to inflammation, Wnt signaling and type I interferon pathways. The presence of a specific transcriptome in whole blood of RA patients suggests the activation of a specific inflammatory transcriptional signature in early RA development. The set of overexpressed genes in early RA patients that are shared with ACCP+ subjects but not with ACCP- subjects, can represent a transcriptional signature involved with the transition of a preclinical to a clinical RA stage. Some of these particular up-regulated and down-regulated genes are related to inflammatory processes and could be considered as biomarker candidates for disease progression in subjects at risk to develop RA.