中国骨伤2025，Vol.38Issue(9)：891-901,11.DOI:10.12200/j.issn.1003-0034.20241216
整合基因组学与代谢组学揭示糖尿病足的遗传基础及潜在治疗靶点
Integrating genomics and metabolomics to reveal the genetic basis and potential therapeutic targets of diabetic foot
摘要
Abstract
ASBTRACT Objective To screen out the key metabolites related to diabetic foot(DF)by integrating genome-wide associa-tion studies(GWAS)and metabolome genome-wide association studies(mGWAS).Methods The literature databases such as PubMed and China national knowledge infrastructure(CNKI),as well as genomics databases such as PAN UKBB,FinnGen,and IEU Open GWAS were systematically retrieved from database estobilishment to November 2024 on DF-related single nu-cleotide polymorphisms and genome-wide association studies.DF-single nucleotide polymorphism-metabolite network was constructed by mGWAS package and mGWAS-Explorer platform.The causal relationship between key factors was evaluated by two-sample Mendelian randomization.The genetic correlation between DF and 575 metabolites(source:IEU Open GWAS)was evaluated by linkage disequilibrium score regression.In vitro experiments were conducted to induce injury of human um-bilical vein endothelial cells with 30 mM glucose and intervene with 20 μM γ-tocopherol.Changes in cell migration,scratch healing and tube formation function were detected.Results Twenty-senen literatures on single nucleotide polymorphism litera-tures and 3 studies on GWAS were included.Genetic analysis results showed DF-related single nucleotide polymorphisms were enriched in vascular endothelial dysfunction-related pathways(such as fluid shear stress and atherosclerosis).The results of metabolic network analysis screened out 19 associated metabolites,among which 12 such as γ-tocopherol and pyruvate had significant genetic correlations with DF.Mendelian randomization suggested matrix metalloproteinase-9(MMP-9)might be a potential driver of DF(β=0.658,P=0.063 8),and the occurrence of DF could reduce the level of high-density lipoprotein(β=-0.002,P=0.015 2).The results of in vitro experiments confirmed that γ-tocopherol could improve endothelial dysfunction induced by high glucose,specifically manifested as an increase in the number of cell migrations,improvement in the scratch healing rate,and recovery of tubule formation ability(P＜0.05).Conclusion DF has a genetic basis centered on vascular en-dothelial dysfunction,and its occurrence can lead to further metabolic disorders.The key single nucleotide polymorphism loci integrated provided molecular markers for the risk stratification of foot ulcers in diabetic patients.In addition,γ-tocopherol has demonstrated clinical application potential as a therapeutic drug for DF by significantly improving the function of vascular en-dothelial cells in a high-glucose environment.关键词
糖尿病足/全基因组关联分析/代谢物全基因组关联分析/单核苷酸/代谢物/遗传Key words
Diabetic foot/Genome-wide association study/Metabolome genome-wide association study/Mononu-cleotide/Metabolites/Heredity分类
医药卫生引用本文复制引用
张艺,陈城,李振东,周海超,李兵,杨云峰..整合基因组学与代谢组学揭示糖尿病足的遗传基础及潜在治疗靶点[J].中国骨伤,2025,38(9):891-901,11.基金项目
国家重点研发计划资助项目(编号:2022YFC2009505)National Key Research and Development Program(No.2022YFC2009505) （编号:2022YFC2009505）
