Jalali Pooya, Rezaee Malihe, Yaghoobi Alireza, Piroozkhah Moein, Zabihi Mohammad Reza, Aliyari Shahram, Salehi Zahra
Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Genomics Inform. 2025 May 15;23(1):12. doi: 10.1186/s44342-025-00045-4.
Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders, including ulcerative colitis (UC) and Crohn's disease, affecting the gastrointestinal tract and is associated with high morbidity and mortality. Accumulating evidence indicates that IBD not only impacts the gastrointestinal tract but also affects multiple extraintestinal organs, which may manifest prior to the diagnosis of IBD. Among these extraintestinal manifestations associated with IBD, primary sclerosing cholangitis (PSC) stands out as a prominent example. PSC is recognized as a progressive cholestatic disorder, characterized by the narrowing of bile ducts, eventual development of liver cirrhosis, end-stage liver disease, and the potential emergence of cholangiocarcinoma. This study aimed to identify the molecular contributors in UC-induced PSC by detecting the essential regulatory genes that are differentially expressed in both diseases.
The common single-nucleotide polymorphisms (SNPs) and differentially expressed genes (DEGs) were detected using DisGeNET and GEO databases, respectively. Then, the top module and hub genes within the protein-protein interaction network were identified. Furthermore, the co-expression network of the top module was constructed using the HIPPIE database. Additionally, the gene regulatory network was constructed based on miRNAs and circRNAs. Finally, we searched the DGIdb database for possible interacting drugs with UC-PSC top module genes.
A total of 132 SNPs and their associated genes were found to be shared between UC and PSC. Gene expression analysis identified 56 common DEGs between the two diseases. Following functional enrichment analysis, 207 significant biological processes (BP), 48 molecular functions (MF), and 8 KEGG pathways, with notable enrichment in mRNA-related processes such as mRNA splicing and RNA binding, were defined. Particularly, the PTPN2 gene was the only gene common between UC and PSC at both the SNP level and the expression level. Additionally, the top cluster of PPI network analysis was consisted of PABPC1, SNRPA1, NOP56, NHP2L1, and HNRNPA2B1 genes. Finally, ceRNA network involving 4 mRNAs, 94 miRNAs, and 200 selected circRNAs was constructed.
The present study provides novel potential candidate genes that may be involved in the molecular association between ulcerative colitis and primary sclerosing cholangitis, resulting in the development of diagnostic tools and therapeutic targets to prevent the progression of PSC from UC.
炎症性肠病（IBD）是一组慢性炎症性疾病，包括溃疡性结肠炎（UC）和克罗恩病，影响胃肠道，且发病率和死亡率较高。越来越多的证据表明，IBD不仅影响胃肠道，还会影响多个肠外器官，这些影响可能在IBD诊断之前就已出现。在这些与IBD相关的肠外表现中，原发性硬化性胆管炎（PSC）是一个突出的例子。PSC被认为是一种进行性胆汁淤积性疾病，其特征是胆管狭窄、最终发展为肝硬化、终末期肝病以及胆管癌的潜在发生。本研究旨在通过检测在两种疾病中差异表达的关键调控基因，确定UC诱导PSC的分子因素。
分别使用DisGeNET和GEO数据库检测常见单核苷酸多态性（SNP）和差异表达基因（DEG）。然后，确定蛋白质-蛋白质相互作用网络中的顶级模块和枢纽基因。此外，使用HIPPIE数据库构建顶级模块的共表达网络。此外，基于miRNA和circRNA构建基因调控网络。最后，我们在DGIdb数据库中搜索与UC-PSC顶级模块基因可能相互作用的药物。
共发现132个SNP及其相关基因在UC和PSC之间共享。基因表达分析确定了两种疾病之间56个常见的DEG。经过功能富集分析，定义了207个显著的生物学过程（BP）、48个分子功能（MF）和8条KEGG通路，在mRNA剪接和RNA结合等与mRNA相关的过程中显著富集。特别是，PTPN2基因是UC和PSC在SNP水平和表达水平上唯一共同的基因。此外，PPI网络分析的顶级聚类由PABPC1、SNRPA1、NOP56、NHP2L1和HNRNPA2B1基因组成。最后，构建了包含4个mRNA、94个miRNA和200个选定circRNA 的ceRNA网络。
本研究提供了可能参与溃疡性结肠炎和原发性硬化性胆管炎分子关联的新的潜在候选基因，从而为开发诊断工具和治疗靶点以预防PSC从UC进展提供了依据。
