Lindblom Julius, Toro-Domínguez Daniel, Carnero-Montoro Elena, Beretta Lorenzo, Borghi Maria Orietta, Castillo Jessica, Enman Yvonne, Mohan Chandra, Alarcón-Riquelme Marta E, Barturen Guillermo, Parodis Ioannis
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
GENYO, Centre for Genomics and Oncological Research: Pfizer, University of Granada / Andalusian Regional Government, Granada, Spain, Medical Genomics, Granada, Spain.
J Autoimmun. 2023 Apr;136:103025. doi: 10.1016/j.jaut.2023.103025. Epub 2023 Mar 28.
We aimed at investigating the whole-blood transcriptome, expression quantitative trait loci (eQTLs), and levels of selected serological markers in patients with SLE versus healthy controls (HC) to gain insight into pathogenesis and identify drug targets.
We analyzed differentially expressed genes (DEGs) and dysregulated gene modules in a cohort of 350 SLE patients and 497 HC from the European PRECISESADS project (NTC02890121), split into a discovery (60%) and a replication (40%) set. Replicated DEGs qualified for eQTL, pathway enrichment, regulatory network, and druggability analysis. For validation purposes, a separate gene module analysis was performed in an independent cohort (GSE88887).
Analysis of 521 replicated DEGs identified multiple enriched interferon signaling pathways through Reactome. Gene module analysis yielded 18 replicated gene modules in SLE patients, including 11 gene modules that were validated in GSE88887. Three distinct gene module clusters were defined i.e., "interferon/plasma cells", "inflammation", and "lymphocyte signaling". Predominant downregulation of the lymphocyte signaling cluster denoted renal activity. By contrast, upregulation of interferon-related genes indicated hematological activity and vasculitis. Druggability analysis revealed several potential drugs interfering with dysregulated genes within the "interferon" and "PLK1 signaling events" modules. STAT1 was identified as the chief regulator in the most enriched signaling molecule network. Drugs annotated to 15 DEGs associated with cis-eQTLs included bortezomib for its ability to modulate CTSL activity. Belimumab was annotated to TNFSF13B (BAFF) and daratumumab was annotated to CD38 among the remaining replicated DEGs.
Modulation of interferon, STAT1, PLK1, B and plasma cell signatures showed promise as viable approaches to treat SLE, pointing to their importance in SLE pathogenesis.
我们旨在研究系统性红斑狼疮（SLE）患者与健康对照（HC）的全血转录组、表达数量性状基因座（eQTL）以及选定血清学标志物的水平，以深入了解发病机制并确定药物靶点。
我们分析了来自欧洲PRECISESADS项目（NTC02890121）的350例SLE患者和497例HC队列中的差异表达基因（DEG）和失调基因模块，将其分为发现集（60%）和复制集（40%）。经过复制的DEG用于eQTL、通路富集、调控网络和药物可及性分析。为了进行验证，在一个独立队列（GSE88887）中进行了单独的基因模块分析。
对521个经过复制的DEG进行分析，通过Reactome鉴定出多个富集的干扰素信号通路。基因模块分析在SLE患者中产生了18个经过复制的基因模块，其中11个基因模块在GSE88887中得到验证。定义了三个不同的基因模块簇，即“干扰素/浆细胞”、“炎症”和“淋巴细胞信号传导”。淋巴细胞信号传导簇的主要下调表示肾脏活动。相比之下，干扰素相关基因的上调表明血液学活动和血管炎。药物可及性分析揭示了几种潜在药物可干扰“干扰素”和“PLK1信号事件”模块内失调的基因。STAT1被确定为最富集的信号分子网络中的主要调节因子。注释到与顺式eQTL相关的15个DEG的药物包括硼替佐米，因其能够调节CTSL活性。在其余经过复制的DEG中，贝利尤单抗注释到TNFSF13B（BAFF），达雷妥尤单抗注释到CD38。
调节干扰素、STAT1、PLK1、B和浆细胞特征显示出有望成为治疗SLE的可行方法，表明它们在SLE发病机制中的重要性。
