Li Yongwei, Liao Xi, Yu Xi, Xiao Ying, Tao Xiaoyu, Zhong Tian
Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China.
Int J Mol Sci. 2025 May 8;26(10):4471. doi: 10.3390/ijms26104471.
This study utilized Mendelian randomization (MR) to investigate the impact of inflammatory proteins on knee osteoarthritis (KOA), measured using the ratio of protein levels (rQTLs). The primary objective was to identify potential intervention targets to mitigate KOA progression. Data from 2821 rQTLs, 91 inflammatory proteins, and KOA-related genetic variations were obtained through genome-wide association studies (GWAS). Bidirectional MR identified rQTLs with unidirectional causal relationships with KOA. Further analyses included false discovery rate (FDR) correction, colocalization, and mediation analysis. Two inflammatory proteins were found to be associated with KOA: T-cell surface glycoprotein CD5 [OR (95% CI) = 0.867 (0.760-0.990), = 0.035] and C-X-C motif chemokine 9 [OR (95% CI) = 1.150 (1.001-1.320), = 0.048]. Variations in their levels influenced rQTLs, producing differential effects on KOA. Specifically, rQTL-ANGPTL3/TFPI (human recombinant angiopoietin-like protein 3/Tissue factor pathway inhibitor) was identified as a mediator in the effect of T-cell surface glycoprotein CD5 levels on KOA. T-cell surface glycoprotein CD5 levels were negatively correlated with rQTL-ANGPTL3/TFPI (1 = -0.084), while rQTL-ANGPTL3/TFPI was positively correlated with KOA (2 = 0.159). These findings align with the total effect, where T-cell surface glycoprotein CD5 levels were negatively associated with KOA ( = -0.143). Thus, rQTL-ANGPTL3/TFPI may serve as a reliable mediator in the pathway through which T-cell surface glycoprotein CD5 levels affect KOA. This mediator may not only represent a potential therapeutic target but also serve as a biomarker for assessing KOA treatment efficacy, offering a novel direction for KOA diagnosis and management.
本研究利用孟德尔随机化（MR）方法，通过蛋白质水平比值（rQTLs）来研究炎症蛋白对膝关节骨关节炎（KOA）的影响。主要目的是确定减轻KOA进展的潜在干预靶点。通过全基因组关联研究（GWAS）获得了来自2821个rQTLs、91种炎症蛋白和KOA相关基因变异的数据。双向MR确定了与KOA具有单向因果关系的rQTLs。进一步的分析包括错误发现率（FDR）校正、共定位和中介分析。发现两种炎症蛋白与KOA相关：T细胞表面糖蛋白CD5 [比值比（95%置信区间）= 0.867（0.760 - 0.990），P = 0.035]和C-X-C基序趋化因子9 [比值比（95%置信区间）= 1.150（1.001 - 1.320），P = 0.048]。它们水平的变化影响rQTLs，对KOA产生不同影响。具体而言，rQTL-ANGPTL3/TFPI（人重组血管生成素样蛋白3/组织因子途径抑制剂）被确定为T细胞表面糖蛋白CD5水平对KOA影响的中介物。T细胞表面糖蛋白CD5水平与rQTL-ANGPTL3/TFPI呈负相关（r1 = -0.084），而rQTL-ANGPTL3/TFPI与KOA呈正相关（r2 = 0.159）。这些发现与总体效应一致，即T细胞表面糖蛋白CD5水平与KOA呈负相关（r = -0.143）。因此，rQTL-ANGPTL3/TFPI可能是T细胞表面糖蛋白CD5水平影响KOA途径中的可靠中介物。这种中介物不仅可能代表一个潜在的治疗靶点，还可作为评估KOA治疗效果的生物标志物，为KOA的诊断和管理提供了新的方向。
