Division of Rheumatology, Department of Internal Medicine, Konkuk University Medical Center, Seoul, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Arthritis Res Ther. 2019 Dec 19;21(1):294. doi: 10.1186/s13075-019-2082-9.
Treatment of patients with Sjögren's syndrome (SjS) is a clinical challenge with high unmet needs. Gene expression profiling and integrative network-based approaches to complex disease can offer an insight on molecular characteristics in the context of clinical setting.
An integrated dataset was created from salivary gland samples of 30 SjS patients. Pathway-driven enrichment profiles made by gene set enrichment analysis were categorized using hierarchical clustering. Differentially expressed genes (DEGs) were subjected to functional network analysis, where the elements of the core subnetwork were used for key driver analysis.
We identified 310 upregulated DEGs, including nine known genetic risk factors and two potential biomarkers. The core subnetwork was enriched with the processes associated with B cell hyperactivity. Pathway-based subgrouping revealed two clusters with distinct molecular signatures for the relevant pathways and cell subsets. Cluster 2, with low-grade inflammation, showed a better response to rituximab therapy than cluster 1, with high-grade inflammation. Fourteen key driver genes appeared to be essential signaling mediators downstream of the B cell receptor (BCR) signaling pathway and to have a positive relationship with histopathology scores.
Integrative network-based approaches provide deep insights into the modules and pathways causally related to SjS and allow identification of key targets for disease. Intervention adjusted to the molecular traits of the disease would allow the achievement of better outcomes, and the BCR signaling pathway and its leading players are promising therapeutic targets.
干燥综合征 (SjS) 患者的治疗是一个具有高度未满足需求的临床挑战。基因表达谱分析和基于整合网络的复杂疾病方法可以提供有关临床背景下分子特征的见解。
从 30 名 SjS 患者的唾液腺样本中创建了一个综合数据集。通过基因集富集分析进行的通路驱动的富集谱使用层次聚类进行分类。差异表达基因 (DEGs) 进行功能网络分析，其中核心子网络的元素用于关键驱动分析。
我们鉴定了 310 个上调的 DEGs，包括九个已知的遗传风险因素和两个潜在的生物标志物。核心子网络富含与 B 细胞过度活跃相关的过程。基于通路的亚组分析显示，两个相关通路和细胞亚群具有不同的分子特征。炎症程度较低的簇 2 对利妥昔单抗治疗的反应优于炎症程度较高的簇 1。14 个关键驱动基因似乎是 B 细胞受体 (BCR) 信号通路下游的重要信号转导介质，并且与组织病理学评分呈正相关。
基于整合网络的方法深入了解与 SjS 因果相关的模块和途径，并确定疾病的关键靶点。针对疾病分子特征的干预措施将允许实现更好的结果，BCR 信号通路及其主要参与者是有前途的治疗靶点。
