Huang Luofei, Li Han, Lin Quanzhi
Liuzhou Municipal Liutie Central Hospital, Liuzhou, Guangxi, China.
Department of Internal Medicine, Liuzhou People's Hospital, Liuzhou, Guangxi, China.
Medicine (Baltimore). 2025 May 23;104(21):e42437. doi: 10.1097/MD.0000000000042437.
Peripheral atherosclerosis (PAS), characterized by lipid plaque accumulation in arterial walls, significantly increases cardiovascular risk. This study aimed to identify molecular biomarkers and elucidate underlying mechanisms of PAS progression. We analyzed 2 gene expression omnibus datasets (GSE28829, GSE100927) to identify differentially expressed genes (P < .05, |log2FC| ≥ 0.585). Functional enrichment (Gene Ontology/Kyoto Encyclopedia of Genes and Genomes) and Mendelian randomization analyses were performed using genome-wide association study and expression quantitative trait loci data. Six hub genes were validated through single-cell RNA sequencing and independent datasets. A diagnostic nomogram was developed and evaluated using calibration curves, decision curve analysis, and receiver operating characteristic metrics. Integrated analysis revealed 6 key PAS-associated genes (leukocyte immunoglobulin-like receptor B1, hematopoietic cell-specific lyn substrate 1, plasminogen activator urokinase, C-type lectin domain family 2 member B, phosphatidylinositol-4-phosphate 5-kinase type 1 beta, cofilin 2). The diagnostic model demonstrated exceptional accuracy, achieving area under the receiver operating characteristic curves of 1.0 (training) and 0.975 (validation). Mendelian randomization confirmed causal relationships, with cofilin 2 and phosphatidylinositol-4-phosphate 5-kinase type 1 beta showing protective effects (odds ratio 0.74-0.90), while C-type lectin domain family 2 member B, hematopoietic cell-specific lyn substrate 1, leukocyte immunoglobulin-like receptor B1, and plasminogen activator urokinase emerged as risk factors. This multi-omics study identifies novel molecular signatures of PAS and establishes a robust diagnostic tool. The findings advance our understanding of PAS pathogenesis and pave the way for personalized therapeutic strategies.
外周动脉粥样硬化（PAS）以动脉壁脂质斑块积聚为特征，显著增加心血管风险。本研究旨在识别分子生物标志物并阐明PAS进展的潜在机制。我们分析了2个基因表达综合数据集（GSE28829、GSE100927）以识别差异表达基因（P < 0.05，|log2FC|≥0.585）。使用全基因组关联研究和表达数量性状位点数据进行功能富集（基因本体论/京都基因与基因组百科全书）和孟德尔随机化分析。通过单细胞RNA测序和独立数据集验证了6个枢纽基因。使用校准曲线、决策曲线分析和受试者工作特征指标开发并评估了诊断列线图。综合分析揭示了6个与PAS相关的关键基因（白细胞免疫球蛋白样受体B1、造血细胞特异性Lyn底物1、尿激酶型纤溶酶原激活剂、C型凝集素结构域家族2成员B、磷脂酰肌醇-4-磷酸5-激酶1β型、丝切蛋白2）。诊断模型显示出卓越的准确性，训练集受试者工作特征曲线下面积为1.0，验证集为0.975。孟德尔随机化证实了因果关系，丝切蛋白2和磷脂酰肌醇-4-磷酸5-激酶1β型显示出保护作用（优势比0.74 - 0.90），而C型凝集素结构域家族2成员B、造血细胞特异性Lyn底物1、白细胞免疫球蛋白样受体B1和尿激酶型纤溶酶原激活剂则为危险因素。这项多组学研究识别了PAS的新分子特征并建立了强大的诊断工具。这些发现增进了我们对PAS发病机制的理解，并为个性化治疗策略铺平了道路。
