摘要
背景:遗传因素在骨质疏松症的病理机制中扮演重要角色,孟德尔随机化可利用eQTL推断特定基因与疾病之间的因果关联。目的:基于可成药基因进行孟德尔随机化和共定位分析,利用生物信息学分析骨质疏松症治疗靶点的潜在生物学机制,并通过药物富集分析和分子对接预测药物靶点的结合活性。方法:①数据来源:可成药基因来源于DGIdb数据库(由华盛顿大学医学院构建的公共数据库,被广泛用于药物靶点发现)和文献中提供的信息;可成药基因的相关表达数量性状位点数据来自于eQTLGen(由荷兰格罗宁根大学等多个国际研究机构合作构建的大型血液eQTL数据库);骨质疏松症的全基因组关联研究数据来自于FinnGen R12(由芬兰赫尔辛基大学主导构建的大型基因组数据库),其中骨质疏松症病例10461例,对照473264例;GEO数据库的GSE230665芯片数据集和GSE169396单细胞数据集。②方法:筛选与骨质疏松症密切相关的基因;通过芯片数据评估基因在骨质疏松症中的具体表达;单细胞分析进一步观察基因在细胞通讯中的调节作用;通过富集分析阐释生物学功能,构建蛋白互作网络以分析潜在关联;药物富集和分子对接预测并模拟小分子药物与靶点的结合。结果与结论:该研究识别出了37个与骨质疏松症相关的可成药基因,其中肌钙蛋白C2、CXC趋化因子受体6在骨质疏松症中具有保护作用且与疾病共享因果遗传变异。芯片数据分析表明,CXC趋化因子受体6在骨质疏松症中的表达较正常组显著降低,提示其在骨质疏松症的保护作用减弱。单细胞分析进一步发现CXC趋化因子受体6主要在T细胞上表达,且CXC趋化因子受体6+T细胞展示出更强的细胞通讯能力。药物富集分析发现NSC95397能够靶向结合CXC趋化因子受体6,分子对接显示其与CXC趋化因子受体6结合活性良好。这些发现不仅为骨质疏松症新型药物的研发提供线索,还有利于促进研究成果的转化应用。
BACKGROUND:Genetic factors play an important role in the pathophysiology of osteoporosis,and Mendelian randomization can be used to infer causal associations between specific genes and diseases using eQTLs.OBJECTIVE:To identify potential therapeutic targets for osteoporosis based on druggable genes-related Mendelian randomization and colocalization analysis,to explore the potential biological mechanisms in the treatment of osteoporosis using bioinformatics analysis,and to predict the binding activity of drug targets using drug enrichment analysis and molecular docking.METHODS:(1)Data sources:Druggable genes were sourced from the DGIdb database(a public database constructed by the University of Washington School of Medicine,widely used for drug target discovery)and information provided in the literature.Expression quantitative trait locus(eQTL)data for druggable genes were obtained from eQTLGen(a large-scale blood eQTL database jointly constructed by multiple international research institutions,including the University of Groningen in the Netherlands).The genome-wide association study data for osteoporosis were obtained from FinnGen R12(a large-scale genomic database led by the University of Helsinki in Finland),including 10461 osteoporosis cases and 473264 controls.GSE230665 chip dataset and GSE169396 single-cell dataset were obtained from the GEO database.(2)Methods:Genes closely associated with osteoporosis were screened.Gene expression specific to osteoporosis was evaluated using array.Single-cell analysis was used to further examine the regulatory role of these genes in cell communication.Additionally,enrichment analysis was performed to elucidate biological functions,and a protein-protein interaction network was constructed to analyze potential associations.Drug enrichment and molecular docking were used to predict and simulate the binding of small molecule drugs with targets.RESULTS AND CONCLUSION:This study identified 37 druggable genes associated with osteoporosis,among which Troponin C2 and CXC chemokine receptor 6 have protective roles in osteoporosis and share causal genetic variations with the disease.Array data analysis showed that CXC chemokine receptor 6 expression was significantly reduced in osteoporosis compared with the normal group,suggesting its diminished protective role in osteoporosis.Single cell analysis further revealed that CXC chemokine receptor 6is predominantly expressed on T cells,and CXC chemokine receptor 6 positive T cells exhibit stronger cell communication abilities.Drug enrichment found that NSC95397 can target and bind CXC chemokine receptor 6,and molecular docking showed good binding activity with CXC chemokine receptor 6.These findings not only provide clues for the development of novel osteoporosis drugs but also promote the translation and application of research outcomes.
作者
李义尉
雒宗明
戎义发
姜凯
张加豪
卢博文
李刚
Li Yiwei;Luo Zongming;Rong Yifa;Jiang Kai;Zhang Jiahao;Lu Bowen;Li Gang(First Clinical Medical College,Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong Province,China;Department of Microsurgical Orthopedics,Affiliated Hospital of Shandong University of Traditional Chinese Medicine,Jinan 250014,Shandong Province,China)
出处
《中国组织工程研究》
北大核心
2026年第25期6654-6660,共7页
Chinese Journal of Tissue Engineering Research
基金
山东省重点研发计划(重大科技创新工程)项目(2021CXGC010501),项目负责人:李刚
领军科创团队(2024sdskctd-02),项目负责人:李刚。
