IntroductionPeripheral vascular atherosclerosis (PVA) is a chronic inflammatory disease characterized by lipid accumulation in blood vessel walls, leading to vessel narrowing and inadequate blood supply. However, the molecular mechanisms underlying PVA remain poorly understood. In this study, we employed a combination of Mendelian randomization (MR) analysis and integrated transcriptomics to identify the critical gene signature associated with PVA.MethodsThis study utilized three public datasets (GSE43292, GSE100927 and GSE28829) related to peripheral vascular atherosclerosis obtained from the Gene Expression Omnibus database. Instrumental variables (IVs) were identified through expression quantitative trait loci (eQTL) analysis, and two-sample MR analysis was performed using publicly available summary statistics. Disease critical genes were identified based on odds ratios and intersected with differentially expressed genes in the disease dataset. GSE28829 dataset was used to validate the screened disease critical genes. Functional enrichment analysis, GSEA analysis, and immune cell infiltration analysis were performed to further characterize the role of these genes in peripheral vascular atherosclerosis.ResultsA total of 26,152 gene-related SNPs were identified as IVs, and 242 disease-associated genes were identified through MR analysis. Ten disease critical genes (ARHGAP25, HCLS1, HVCN1, RBM47, LILRB1, PLAU, IFI44L, IL1B, IFI6, and CFL2) were significantly associated with peripheral vascular atherosclerosis. Functional enrichment analysis using KEGG pathways revealed enrichment in the NF-kappa B signaling pathway and osteoclast differentiation. Gene set enrichment analysis further demonstrated functional enrichment of these genes in processes related to vascular functions and immune system activation. Additionally, immune cell infiltration analysis showed differential ratios of B cells and mast cells between the disease and control groups. The correlations analysis highlights the intricate interplay between disease critical genes and immune cells associated with PVA.ConclusionIn conclusion, this study provides new insights into the molecular mechanisms underlying PVA by identifying ten disease critical genes associated with the disease. These findings, supported by differential expression, functional enrichment, and immune system involvement, emphasize the role of these genes in vascular function and immune cell interactions in the context of PVA. These findings contribute to a better understanding of PVA pathogenesis and offer potential targets for further mechanistic exploration and therapeutic interventions.

中文翻译：

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外周血管动脉粥样硬化的关键基因特征和免疫学特征：孟德尔随机化和转录组学的新见解

简介外周血管动脉粥样硬化（PVA）是一种慢性炎症性疾病，其特征是血管壁脂质积聚，导致血管狭窄和血液供应不足。然而，PVA 的分子机制仍然知之甚少。在这项研究中，我们结合了孟德尔随机化 (MR) 分析和整合转录组学来识别与 PVA 相关的关键基因特征。 方法这项研究利用了从基因中获得的与外周血管动脉粥样硬化相关的三个公共数据集（GSE43292、GSE100927 和 GSE28829）。表达式综合数据库。通过表达数量性状位点 (eQTL) 分析确定工具变量 (IV)，并使用公开的汇总统计数据进行两样本 MR 分析。根据比值比确定疾病关键基因，并与疾病数据集中的差异表达基因相交。 GSE28829数据集用于验证筛选的疾病关键基因。通过功能富集分析、GSEA分析和免疫细胞浸润分析，进一步表征这些基因在外周血管动脉粥样硬化中的作用。结果共鉴定出26,152个基因相关SNP作为IV，通过MR鉴定出242个疾病相关基因分析。十个疾病关键基因（ARHGAP25、HCLS1、HVCN1、RBM47、LILRB1、PLAU、IFI44L、IL1B、IFI6 和 CFL2）与外周血管动脉粥样硬化显着相关。使用 KEGG 通路的功能富集分析揭示了 NF-kappa B 信号通路和破骨细胞分化的富集。基因集富集分析进一步证明了这些基因在与血管功能和免疫系统激活相关的过程中的功能富集。此外，免疫细胞浸润分析显示疾病组和对照组之间 B 细胞和肥大细胞的比例存在差异。相关性分析强调了与 PVA 相关的疾病关键基因和免疫细胞之间复杂的相互作用。 结论 总之，本研究通过识别与疾病相关的 10 个疾病关键基因，为 PVA 的分子机制提供了新的见解。这些发现得到差异表达、功能富集和免疫系统参与的支持，强调了这些基因在 PVA 背景下血管功能和免疫细胞相互作用中的作用。这些发现有助于更好地了解 PVA 发病机制，并为进一步的机制探索和治疗干预提供潜在目标。