Compendium of skin molecular signatures identifies key pathological features associated with fibrosis in systemic sclerosis

医学 简编 病态的 纤维化 病理 多发性硬化 硬皮病(真菌) 生物信息学 皮肤病科 免疫学 生物 历史 考古 接种
作者
Su‐Jin Moon,Jung Min Bae,Kyung-Su Park,Ilias Tagkopoulos,Ki‐Jo Kim
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:78 (6): 817-825 被引量:36
标识
DOI:10.1136/annrheumdis-2018-214778
摘要

Objectives Treatment of patients with systemic sclerosis (SSc) can be challenging because of clinical heterogeneity. Integration of genome-scale transcriptomic profiling for patients with SSc can provide insights on patient categorisation and novel drug targets. Methods A normalised compendium was created from 344 skin samples of 173 patients with SSc, covering an intersection of 17 424 genes from eight data sets. Differentially expressed genes (DEGs) identified by three independent methods were subjected to functional network analysis, where samples were grouped using non-negative matrix factorisation. Finally, we investigated the pathways and biomarkers associated with skin fibrosis using gene-set enrichment analysis. Results We identified 1089 upregulated DEGs, including 14 known genetic risk factors and five potential drug targets. Pathway-based subgrouping revealed four distinct clusters of patients with SSc with distinct activity signatures for SSc-relevant pathways. The inflammatory subtype was related to significant improvement in skin fibrosis at follow-up. The phosphoinositide-3-kinase-protein kinase B (PI3K-Akt) signalling pathway showed both the closest correlation and temporal pattern to skin fibrosis score. COMP , THBS1 , THBS4 , FN1 , and TNC were leading-edge genes of the PI3K-Akt pathway in skin fibrogenesis. Conclusions Construction and analysis of normalised skin transcriptomic compendia can provide useful insights on pathway involvement by SSc subsets and discovering viable biomarkers for a skin fibrosis index. Particularly, the PI3K-Akt pathway and its leading players are promising therapeutic targets.
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