Causal relationship between 91 inflammatory proteins and cervical disc degeneration

doi:10.12307/2025.644

Abstract

Abstract: BACKGROUND: Cervical disc degeneration is a common degenerative disease, and inflammatory proteins play an important role in cervical disc degeneration, but the specific mechanisms involved remain to be thoroughly investigated.
OBJECTIVE: Using the Mendelian randomization method to assess the potential causal relationship between 91 inflammatory proteins and cervical disc degeneration.
METHODS: Genome-wide association analysis statistics for 91 inflammatory proteins (from GCST90274758 to GCST90274848) were obtained from the Genome-Wide Association Analysis Catalog of publicly available genome-wide association analysis data and genome-wide association analysis data for cervical disc degeneration from the Finngen database (finngen_R10_M13_CERVICDISCV). Inverse variance weighting, MR-Egger regression, weighted median, weighted modeling, and simple modeling were used to investigate the causal relationship between inflammatory proteins and cervical disc degeneration. Sensitivity analyses were performed to test whether the results of the Mendelian randomization analysis were reliable, and then the inverse Mendelian randomization analysis was performed in the same way.
RESULTS AND CONCLUSION: The results of the forward analysis showed that a total of six inflammatory proteins were significantly and causally associated with cervical disc degeneration, of which glial cell lineage-derived neurotrophic factor (odds ratio (OR)=1.095, 95% confidence interval (CI): 1.012-1.184, P=0.023), interleukin 4 (OR=1.094, 95% CI: 1.002-1.194, P=0.045) and monocyte chemotactic protein-1 levels (OR=1.062, 95% CI: 1.001-1.127, P=0.048) showed a direct positive causal association with the risk of cervical disc degeneration; interleukin 17C (OR=0.906, 95% CI: 0.839-0.979, P=0.013), interleukin 18 (OR=0.924, 95% CI: 0.866-0.986, P=0.017) and interleukin 2 levels (OR=0.894, 95% CI: 0.821-0.973, P=0.010) showed a direct negative causal association with the risk of cervical disc degeneration. The results of the inverse analysis showed that when cervical disc degeneration was used as exposure data, there was no significant causal relationship with any of the 91 inflammatory proteins. The results of the sensitivity analysis showed that the Cochran’s Q test for the two-way Mendelian randomization, the MR-Egger regression method, and the MR-PRESSO results had P values greater than 0.05, indicating that there was no significant heterogeneity or multiplicity in the analysis of the causal effect between inflammatory proteins and cervical disc degeneration. To conclude, there may be a relatively significant potential causal relationship between glial cell line-derived neurotrophic factor, interleukin 4, monocyte chemotactic protein-1, interleukin 17C levels, interleukin 18, and interleukin 2 levels and cervical disc degeneration, which provides valuable clues for research on the potential mechanisms of cervical disc degeneration as well as early prevention and drug treatment of cervical disc degeneration.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: cervical disc degeneration, degenerative disease, inflammatory protein, Mendelian randomization, causality, genetics, genome-wide association studies, single nucleotide polymorphism

CLC Number:

Liu Shuaiyi, Zhao Xiaoxuan, Li Qi, Xing Zheng, Li Qingwen, Chu Xiaolei. Causal relationship between 91 inflammatory proteins and cervical disc degeneration[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(17): 3732-3740.

Figures/Tables 4

2.1 工具变量的选取结果 91个炎症蛋白共纳入2 337个SNPs，F值范围为19.513-3 469.481，均符合F > 10，说明文章具有弱工具变量偏倚的可能性较小。将过滤后的相关工具变量，与结局数据进行孟德尔随机化分析。 2.2 炎症蛋白对颈椎间盘退变的因果效应文章以IVW方法为主要分析方法，发现3种炎症蛋白与颈椎间盘退变呈正相关，另外3种炎症蛋白与颈椎间盘退变呈负相关，见图2，3。IVW方法分析结果显示，胶质细胞系源性神经营养因子水平(glial cell line-derived neurotrophic factor levels，GDNF)(OR=1.095，95%CI：1.012-1.184，P=0.023)、白细胞介素4水平(OR= 1.094，95%CI：1.002-1.194，P=0.045)、单核细胞趋化蛋白1水平(monocyte chemoattractant protein-1 levels，MCP-1)(OR=1.062，95%CI：1.001-1.127，P=0.048)与颈椎间盘退变之间存在正向因果效应；白细胞介素17 C水平(OR=0.906，95%CI：0.839-0.979，P=0.013)、白细胞介素18水平(OR=0.924，95%CI：0.866-0.986，P=0.017)、白细胞介素2水平(OR=0.894，95%CI：0.821-0.973，P=0.010)与颈椎间盘退变之间存在负向因果效应。此外，文章还使用了MR-Egger回归、加权中位数法、简单模型法、加权模型法对IVW方法的结果进行补充验证，结果显示其他4种方法结果的方向与IVW方法一致，见图4。文章进行了一系列敏感性分析，以检验结果是否存在异质性和水平多效性，见表2。根据Cochran’s Q检验结果，没有观察到显著的异质性(P > 0.05)。同时MR-Egger回归的截距均接近于0且检验P值均> 0.05，MR-PRESSO方法结果未检测到离群值，表示结果不存在水平多效性。此外，留一法检验分析显示，在逐个剔除单核苷酸多态性后结果相对稳定，无单核苷酸多态性对因果关系具有较大影响，见图5。 2.3 颈椎间盘退变对炎症蛋白的因果效应文章对颈椎间盘退变与91种炎症蛋白进行反向孟德尔随机化分析，分析结果的P值均> 0.05，表明颈椎间盘退变与91种炎症蛋白均不具有反向因果关系，进一步验证了正向孟德尔随机化分析得出的结果。"

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