Nie Hongfei, Hu Xiao, Wang Jiaxiao, Wang Jia, Yu Xiaoqian, Li Jun
Department of Pain Management, West China Hospital Sichuan University Chengdu Sichuan Province China.
Frontiers Science Center for Disease-Related Molecular Network, Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital Sichuan University Chengdu Sichuan Province China.
JOR Spine. 2025 Mar 24;8(1):e70057. doi: 10.1002/jsp2.70057. eCollection 2025 Mar.
Intervertebral disc degeneration (IDD) is a major cause of cervical and lumbar diseases, significantly impacting patients' quality of life. Mitochondria and cell death have been implicated in IDD, but the key related genes remain unknown.
Differentially expressed genes (DEGs) between IDD and control samples were identified using GSE70362. Mitochondria-related genes (MRGs) and programmed cell death-related genes (PCDRGs) were intersected with DEGs to find DE-MRGs and DE-PCDRGs. Weighted gene co-expression network analysis (WGCNA) identified key module genes, and the overlap with DEGs revealed candidate genes. Mendelian randomization (MR) analysis was used to determine genes causally linked to IDD. Machine learning and expression validation further refined key genes, which were then used to build a nomogram to predict IDD risk. Additionally, gene set enrichment analysis (GSEA), immune infiltration, and single-cell analysis were performed.
A total of 515 DEGs were intersected with 224 key module genes, yielding 31 candidate genes. Six genes-BCKDHB, BID, TNFAIP6, VRK1, CAB39L, and TMTC1-showed a causal relationship with IDD. BID, TNFAIP6, and TMTC1 were further identified as key genes through machine learning and validation. A nomogram was developed based on these genes. GSEA revealed BID and TMTC1 were enriched in N-glycan biosynthesis, TNFAIP6 and TMTC1 in aminoacyl tRNA biosynthesis, and BID and TMTC1 in ribosomal pathways. Activated dendritic cells, CD56dim natural killer cells, monocytes, and other immune cells were elevated in IDD, with TNFAIP6 strongly correlating with activated dendritic cells. Key genes were expressed at higher levels in degraded samples.
BID, TMTC1, and TNFAIP6 were identified as key genes linked to mitochondria and cell death in IDD, offering new insights for diagnosis and treatment.
椎间盘退变（IDD）是颈腰椎疾病的主要原因，严重影响患者的生活质量。线粒体和细胞死亡与IDD有关，但关键相关基因仍不清楚。
利用GSE70362鉴定IDD样本与对照样本之间的差异表达基因（DEG）。将线粒体相关基因（MRG）和程序性细胞死亡相关基因（PCDRG）与DEG进行交集分析，以找到差异表达的线粒体相关基因（DE-MRG）和差异表达的程序性细胞死亡相关基因（DE-PCDRG）。加权基因共表达网络分析（WGCNA）确定关键模块基因，并将其与DEG的重叠部分揭示候选基因。采用孟德尔随机化（MR）分析来确定与IDD有因果关系的基因。机器学习和表达验证进一步优化关键基因，然后用这些基因构建列线图以预测IDD风险。此外，还进行了基因集富集分析（GSEA）、免疫浸润分析和单细胞分析。
共515个DEG与224个关键模块基因进行交集分析，产生31个候选基因。6个基因——BCKDHB、BID、TNFAIP6、VRK1、CAB39L和TMTC1——与IDD存在因果关系。通过机器学习和验证，进一步确定BID、TNFAIP6和TMTC1为关键基因。基于这些基因开发了列线图。GSEA显示，BID和TMTC1在N-聚糖生物合成中富集，TNFAIP6和TMTC1在氨酰tRNA生物合成中富集，BID和TMTC1在核糖体途径中富集。IDD中活化的树突状细胞、CD56dim自然杀伤细胞、单核细胞和其他免疫细胞升高，TNFAIP6与活化的树突状细胞强烈相关。关键基因在退变样本中表达水平较高。
BID、TMTC1和TNFAIP6被确定为与IDD中线粒体和细胞死亡相关的关键基因，为诊断和治疗提供了新的见解。
