DataSheet_3_Exploration of the core pathway of inflammatory bowel disease complicated with metabolic fatty liver and two-sample Mendelian randomization study of the causal relationships behind the disease.docx

BackgroundInflammatory bowel disease (IBD) is often associated with complex extraintestinal manifestations. The incidence of nonalcoholic fatty liver disease (NAFLD) in IBD populations is increasing yearly. However, the mechanism of interaction between NAFLD and IBD is not clear. Consequently, this study aimed to explore the common genetic characteristics of IBD and NAFLD and identify potential therapeutic targets.
Materials and methodsGene chip datasets for IBD and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules in those datasets related to IBD and NAFLD. ClueGO was used for biological analysis of the shared genes between IBD and NAFLD. Based on the Human MicroRNA Disease Database (HMDD), microRNAs (miRNAs) common to NAFLD and IBD were obtained. Potential target genes for the miRNAs were predicted using the miRTarbase, miRDB, and TargetScan databases. Two-sample Mendelian randomization (MR) and two-way MR were used to explore the causal relationship between Interleukin-17 (IL-17) and the risk of IBD and NAFLD using data from GWAS retrieved from an open database.
ResultsThrough WGCNA, gene modules of interest were identified. GO enrichment analysis using ClueGO suggested that the abnormal secretion of chemokines may be a common pathophysiological feature of IBD and NAFLD, and that the IL-17-related pathway may be a common key pathway for the pathological changes that occur in IBD and NAFLD. The core differentially expressed genes (DEGs) in IBD and NAFLD were identified and included COL1A1, LUM, CCL22, CCL2, THBS2, COL1A2, MMP9, and CXCL8. Another cohort was used for validation. Finally, analysis of the miRNAs identified potential therapeutic targets. The MR results suggested that although there was no causal relationship between IBD and NAFLD, there were causal relationships between IL-17 and IBD and NAFLD.
ConclusionWe established a comorbid model to explain the potential mechanism of IBD with NAFLD and identified the chemokine-related pathway mediated by cytokine IL-17 as the core pathway in IBD with NAFLD, in which miRNA also plays a role and thus provides potential therapeutic targets.

【背景】炎症性肠病（Inflammatory Bowel Disease, IBD）常伴随复杂的肠外表现。IBD人群中非酒精性脂肪性肝病（Nonalcoholic Fatty Liver Disease, NAFLD）的发病率逐年升高。然而，NAFLD与IBD之间的相互作用机制尚不明确。本研究旨在探究IBD与NAFLD共有的遗传特征，并筛选潜在治疗靶点。【材料与方法】本研究从基因表达综合数据库（Gene Expression Omnibus, GEO）中获取IBD与NAFLD的基因芯片数据集。通过加权基因共表达网络分析（Weighted Gene Co-expression Network Analysis, WGCNA）在上述数据集中筛选与IBD、NAFLD相关的基因模块。采用ClueGO工具对IBD与NAFLD的共有基因进行生物学功能注释分析。基于人类微小RNA疾病数据库（Human MicroRNA Disease Database, HMDD），获取NAFLD与IBD共有的微小RNA（microRNAs, miRNAs）。利用miRTarbase、miRDB及TargetScan数据库预测这些miRNAs的潜在靶基因。通过公开数据库中检索得到的全基因组关联研究（Genome-Wide Association Study, GWAS）数据，采用双样本孟德尔随机化（Two-sample Mendelian Randomization, MR）及双向孟德尔随机化分析，探究白细胞介素-17（Interleukin-17, IL-17）与IBD、NAFLD发病风险之间的因果关联。【结果】通过WGCNA分析，本研究筛选得到目标基因模块。ClueGO的GO富集分析结果显示，趋化因子分泌异常可能是IBD与NAFLD共有的病理生理特征，而IL-17相关通路可能是二者病理改变的共同关键通路。本研究鉴定得到IBD与NAFLD的核心差异表达基因（Differentially Expressed Genes, DEGs），包括COL1A1、LUM、CCL22、CCL2、THBS2、COL1A2、MMP9及CXCL8。通过独立队列对上述结果进行了验证。最终，通过miRNA分析筛选得到潜在治疗靶点。孟德尔随机化分析结果显示，尽管IBD与NAFLD之间未发现明确因果关联，但IL-17与IBD、NAFLD的发病风险存在因果关联。【结论】本研究构建了IBD合并NAFLD的共病模型以阐释二者潜在的发病机制，明确了由细胞因子IL-17介导的趋化因子相关通路为IBD合并NAFLD的核心通路，且miRNA在该通路中发挥调控作用，本研究结果可为相关治疗提供潜在靶点。