CXCL12可作为2型糖尿病合并慢性阻塞性肺疾病的潜在治疗靶点  

CXCL12 is a potential therapeutic target for type 2 diabetes mellitus complicated by chronic obstructive pulmonary disease

作　　者：许怀文 翁丽 薛鸿[2] XU Huaiwen;WENG Li;XUE Hong(Department of Clinical Medicine,Fujian Medical University,Fuzhou 350122,China;Provincial School of Clinical Medicine,Fujian Medical University,Department of Respiratory and Critical Care Medicine,Fujian Provincial Hospital of Fujian Medical University,Fuzhou University Affiliated Provincial Hospital,Fuzhou 350001,China)

机构地区：[1]福建医科大学临床医学部,福建福州350122 [2]福建医科大学省立临床医学院//福建省立医院//福州大学附属省立医院呼吸及危重症医学科,福建福州350001

出　　处：《南方医科大学学报》2025年第1期100-109,共10页Journal of Southern Medical University

基　　金：福建省卫生健康科技计划(2019-ZQN-5);福建医科大学启航基金(2018QH1137);福建省卫健委健康科研项目(2021QNA004)。

摘　　要：目的探讨2型糖尿病与慢性阻塞性肺疾病(COPD)的关键基因与免疫学共同机制,并研究潜在的治疗靶点。方法利用基因表达综合数据库(GEO)获取COPD与T2DM的基因表达谱。筛选出共同差异表达基因,并对其进行富集分析和蛋白-蛋白相互网络构建后,综合4种拓扑算法与Friends分析得到候选基因。进行数据集和疾病验证集中候选基因的差异表达验证,得到最终靶点基因,通过受试者工作特征曲线(ROC)评估诊断特征的准确性,通过临床收集的共患病患者资料和血液标本验证靶基因的表达和肺功能相关性。基于CIBERSORT算法分析数据集样品中22种免疫细胞丰度,通过相关性分析靶点基因与22种免疫细胞的关系。使用DGIdb数据库筛选药物-基因互作关系信息和可药用的基因。最后对进行基因集富集分析。结果选取两种疾病175个共同差异表达基因进分析,结果显示其主要富集于免疫与炎症相关通路,最终筛选趋化因子配体12(CXCL12)作为最终靶基因,其表达在两种疾病中均明显上升(P<0.05),且在ROC曲线中表现出较优异效能,并在COPD共患2型糖尿病患者的血液得到验证。CXCL12表达与肺功能的相关性也得到验证。免疫浸润分析结果显示,CXCL12与CD8+T细胞、γδT细胞和静息肥大细胞呈正相关,而与静息NK细胞和嗜酸性粒细胞呈负相关,差异均具有统计学意义(P<0.01)。GESA分析显示“细胞因子-细胞因子受体相互作用”为与CXCL12高表达密切相关的活化途径。药物-基因检测显示,与CXCL12相关的药物多为非靶向,有较大的细胞毒性,还有进一步改良的空间。结论CXCL12可能是COPD与T2DM共同的关键发病基因,靶向CXCL12药物可能是未来COPD和T2DM共病患者更为合理、有效的药物治疗新方向。Objective To identify the key genes and immunological pathways shared by type 2 diabetes mellitus(T2DM)and chronic obstructive pulmonary disease(COPD)and explore the potential therapeutic targets of T2DM complicated by COPD.Methods GEO database was used for analyzing the gene expression profiles in T2DM and COPD to identify the common differentially expressed genes(DEGs)in the two diseases.A protein-protein interaction network was constructed to identify the candidate hub genes,which were validated in datasets and disease sets to obtain the target genes.The diagnostic accuracy of these target genes was assessed with ROC analysis,and their expression levels and association with pulmonary functions were investigated using clinical data and blood samples of patients with T2DM and COPD.The abundance of 22 immune cells was analyzed with CIBERSORT algorithm,and their relationship with the target genes was examined using correlation analysis.DGIdb database was used for analyzing the drug-gene interactions and the druggable genes followed by gene set enrichment analysis.Results We identified a total of 175 common DEGs in T2DM and COPD,mainly enriched in immuneand inflammation-related pathways.Among these genes,CXCL12 was identified as the final target gene,whose expression was elevated in both T2DM and COPD(P<0.05)and showed good diagnostic efficacy.Immune cell infiltration correlation analysis showed significant correlations of CXCL12 with various immune cells(P<0.01).GESA analysis showed that high CXCL12 expression was significantly correlated with"cytokine-cytokine receptor interaction".Drug-gene analysis showed that most of CXCL12-related drugs were not targeted drugs with significant cytotoxicity.Conclusion CXCL12 is a potential common key pathogenic gene of COPD and T2DM,and small-molecule targeted drugs against CXCL12 can provide a new strategy for treatment T2DM complicated by COPD.

关 键 词：2型糖尿病 慢性阻塞性肺疾病 生物信息学分析 趋化因子配体12 靶点分析 

分 类 号：R563.9[医药卫生—呼吸系统] R587.1[医药卫生—内科学]