Reactome pathway analysis from whole-blood transcriptome reveals unique characteristics of systemic sclerosis patients at the preclinical stage.
Reactome pathway analysis from whole-blood transcriptome reveals unique characteristics of systemic sclerosis patients at the preclinical stage.
复制标题
DOI：
10.3389/fimmu.2023.1266391
复制
发表时间：
2023
影响因子：
7.3
通讯作者：
Beretta, Lorenzo
中科院分区：
文献类型：
--
作者：
Bellocchi, Chiara;Wang, Xuan;Lyons, Marka A.;Marchini, Maurizio;Lorini, Maurizio;Carbonelli, Vincenzo;Montano, Nicola;Assassi, Shervin;Beretta, Lorenzo
本研究旨在描述临床前系统性硬化症（PreSSc）受试者的差异表达途径（DEP），其特征在于雷诺现象，特异性自身抗体和/或硬皮病模式的毛细血管镜检查阳性。通过RNA测序分析了33例具有临床前瞻性数据（基线和4年随访后）的PreSSc和16例匹配的健康对照（HC）的全血样本，以进行全局基因表达转录组分析。个体微阵列表达方法注释的Reactome个体化途径的功能分析。方差分析确定DEP的预测能力进行了广泛的内部验证后，在逻辑回归模型进行了测试。4年时，42.4%的受试者发生进展（PreSSc进展），而其他受试者保持稳定的PreSSc临床特征（稳定的PreSSc）。在基线时，在831条通路中，541条DEP在错误发现率<0.05时具有显著性，在回归模型中区分PreSSc与HC，AUROC = 0.792 ± 0.242。通过无监督聚类确定了四个临床组（HC、具有HC样特征的HC和PreSSc、具有PreSSc样特征的PreSSc和HC以及PreSSc）。生物学特征随着疾病进展而改变，而在稳定受试者中保持不变。变化幅度与基线聚类相关，但基线DEP不能预测疾病进展。疾病进展主要与信号转导途径的变化有关，特别是与钙相关事件和肌醇1，4，5-三磷酸代谢有关。与HC相比，PreSSc具有独特的Reactome途径特征。进展为明确的SSc的特征是生物学指尖的变化。促进内皮损伤和血管病变的钙相关事件可能与疾病进展相关。
This study aims to characterize differential expressed pathways (DEP) in subjects with preclinical systemic sclerosis (PreSSc) characterized uniquely by Raynaud phenomenon, specific autoantibodies, and/or capillaroscopy positive for scleroderma pattern. Whole-blood samples from 33 PreSSc with clinical prospective data (baseline and after 4 years of follow-up) and 16 matched healthy controls (HC) were analyzed for global gene expression transcriptome analysis via RNA sequencing. Functional Analysis of Individual Microarray Expression method annotated Reactome individualized pathways. ANOVA analysis identified DEP whose predictive capability were tested in logistic regression models after extensive internal validation. At 4 years, 42.4% subjects progressed (evolving PreSSc), while the others kept stable PreSSc clinical features (stable PreSSc). At baseline, out of 831 pathways, 541 DEP were significant at a false discovery rate <0.05, differentiating PreSSc versus HC with an AUROC = 0.792 ± 0.242 in regression models. Four clinical groups were identified via unsupervised clustering (HC, HC and PreSSc with HC-like features, PreSSc and HC with PreSSc-like features, and PreSSc). Biological signatures changed with disease progression while remaining unchanged in stable subjects. The magnitude of change was related to the baseline cluster, yet no DEP at baseline was predictive of progression. Disease progression was mostly related to changes in signal transduction pathways especially linked to calcium-related events and inositol 1,4,5-triphosphate metabolism. PreSSc had distinguished Reactome pathway signatures compared to HC. Progression to definite SSc was characterized by a shift in biological fingertips. Calcium-related events promoting endothelial damage and vasculopathy may be relevant to disease progression.
登录
查看更多内容
DOI：
10.1016/s0140-6736(22)01692-0
发表时间：
2023-01-28
期刊：
Lancet (London, England)
影响因子：
--
作者：
通讯作者：
--
影响因子：
27.4
作者：
van den Hoogen, Frank;Khanna, Dinesh;Pope, Janet E.
通讯作者：
Pope, Janet E.
影响因子：
25.4
作者：
Bellando-Randone, Silvia;Del Galdo, Francesco;Matucci-Cerinic, Marco
通讯作者：
Matucci-Cerinic, Marco
影响因子：
--
作者：
Koenig, Martial;Joyal, France;Senecal, Jean-Luc
通讯作者：
Senecal, Jean-Luc
硝苯地平通过激活核因子 erythroid-2 相关因子 2 通路抑制氧化应激并改善骨关节炎
影响因子：
6.1
作者：
Yao, Jun;Long, Huiping;Li, Jia
通讯作者：
Li, Jia