Potential target genes for spondylolisthesis: drugable genome analysis based on the European population-based biodatabase

doi:10.12307/2026.595

Abstract

Abstract: BACKGROUND: Spondylolisthesis is a common disease, and there is a lack of effective drugs to treat it. There is still a need to further define the pathogenesis and screen out more suitable therapeutic targets for spondylolisthesis. Mendelian randomization analysis can be used to explore the drugable genes associated with spondylolisthesis and provide valuable guidance for the development of more effective and targeted therapeutic drugs.
OBJECTIVE: To explore potential therapeutic targets and effective drugs for spondylolisthesis by means of pharmaceutically available genome-wide Mendelian randomization analysis.
METHODS: Using the Finnish database, eQTLGen consortium, drug signature database, drug-gene interaction database, protein-protein interaction database, organic small molecule biological activity database and protein structure database, which contains genome and health information of half a million Finns, data on druggable genes were subjected to two-sample Mendelian randomization analysis and co-localization analysis with data from genome-wide association studies of spondylolisthesis to identify genes highly associated with spondylolisthesis. In addition, GO and KEGG enrichment analysis, protein network construction, drug prediction and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic agents.
RESULTS AND CONCLUSION: In this study, we identified 34 potential drug target genes that were significantly associated with spondylolisthesis, particularly the gene APOBEC3G. This gene showed a significant association with spondylolisthesis outcomes through Mendelian analysis and co-localization analysis, suggesting that APOBEC3G may be a priority therapeutic target. As for other potential mechanisms and drugs, we still need to conduct more in-depth research to determine their roles. This study used a database from a European population, which can be used as a reference for the study of population genetics in China.

Key words: co-localization analysis, spondylolisthesis, Dsigbd database, drugable genes, whole genome-wide association studies

CLC Number:

Zhang Qingfeng, Wang Chaoyi, Yang Jingyan, Li Hanyu, Zhao Yuyang, Hao Huatao, Yu Dong. Potential target genes for spondylolisthesis: drugable genome analysis based on the European population-based biodatabase[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(6): 1592-1601.

Figures/Tables 9

2.1 可成药基因组从DGIdb获得了5 012个可成药基因。此外，从FINAN等[16]综述中获得了4 463个可成药基因。整合数据后，获得了6 888个由人类基因组组织基因命名委员会命名的独特可成药基因，以供后续分析。 2.2 孟德尔随机化分析及有效基因的筛选此次研究共筛选出来34个显著潜在基因，具体数据细节见表1，将其进行可视化，见图1。 2.3 共定位分析结果在34个显著基因中，APOBEC3G的PPH4为0.761，APOBEC3G和脊椎滑脱均可被rs111381709驱动，结果表明APOBEC3G与脊椎滑脱有着较强的关联性，将该结果进行可视化，见图2。 2.4 显著基因功能分析对34个潜在靶点进行GO富集分析，可以看出这些靶点共参与340项生物过程、涉及19个细胞成分、包括37个分子功能。其中，主要参与的生物过程有泌尿生殖系统发育(GO:0001655)、肾脏发育(GO:0001822、GO:0072001)、骨髓细胞分化(GO:0030099)；主要细胞成分有分泌颗粒与分泌颗粒腔(GO:0034774、GO:0030141)、细胞质囊与囊泡腔(GO:0060205、GO:0031983)；主要分子功能包括肝素结合(GO:0008201)、糖胺聚糖结合(GO:0005539)、硫化合物结合(GO:1901681)，见图3。 KEGG通路富集展示了脊椎滑脱相关的显著可成药基因的8条潜在治疗通路，根据富集在每个药物上基因的数目及显著性，排名前5的是钙离子信号通路、丝裂原活化蛋白激酶信号通路(mitogen-activated protein kinase，MAPK)、血管内皮生长因子信号通路(vascular endothelial growth factor，VEGF)、B细胞受体信号通路、胰腺分泌，见图4。 2.5 蛋白互作网络分析将34个显著基因构建蛋白互作网络，隐藏网络中断开的网络节点后，共得到34个节点和57个边缘，平均节点度：3.35，预期边数：49，蛋白互作富集P值：0.15，网络互动量明显高于预期。将结果导出并进行可视化，见图5。 2.6 药物富集结果将34个显著基因与DSigDB数据库下载的数据进行富集分析后，得到19个药物，将以上结果进行可视化，见图6，并选取其中2个显著富集的药物进行分子对接，见表2。"

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