孟德尔随机化分析揭示炎症因子在BMI-视网膜色素变性因果关联中的中介作用

Mendelian Randomization Analysis Identifies Inflammatory Cytokines as Mediators in the Causal Relationship between BMI and Retinitis Pigmentosa

摘要: 目的：探讨体质指数(body mass index, BMI)与视网膜色素变性(retinitis pigmentosa, RP)之间的因果关联，并分析炎症因子在二者关联中的中介作用，以阐明其潜在生物学机制，为RP的预防和治疗提供依据。方法：采用双样本孟德尔随机化(Mendelian randomization, MR)分析，以遗传变异作为工具变量，评估BMI与RP之间的因果关联；进一步采用两步MR方法分析炎症因子在BMI与RP关联中的中介作用。研究数据来源于多个全基因组关联研究(genome-wide association studies, GWAS)的汇总统计数据，研究对象均为欧洲人群。纳入分析的变量包括BMI、RP及91种炎症因子，并通过敏感性分析检验结果的稳健性。结果：BMI与RP之间存在显著正向因果关联[逆方差加权法(inverse variance weighted, IVW)：OR = 1.419, 95% CI: 1.211~1.664, P < 0.001]，反向MR分析未发现RP对BMI的反向因果作用。进一步分析显示，白细胞介素-2 (interleukin-2, IL-2)和血管内皮生长因子A (vascular endothelial growth factor A, VEGF-a)在BMI与RP的关联中具有中介作用，其中中介效应值分别为β = 0.025 (中介比例为7.24%)和β = 0.014 (中介比例为3.86%)。敏感性分析结果表明，研究结论稳健，未见明显多效性或异质性。结论：BMI可能通过慢性炎症和代谢失调影响RP的发生发展，其中IL-2和VEGF-a可能在这一过程中发挥中介作用。上述结果为进一步阐明RP的发病机制及探索相关干预靶点提供了参考。

Abstract: Objective: This study aims to evaluate the causal relationship between body mass index (BMI) and retinitis pigmentosa (RP), while exploring the mediating role of inflammatory factors in this relationship. The goal is to uncover potential biological mechanisms and offer new insights for the prevention and treatment of RP. Methods: A two-sample Mendelian randomization (MR) analysis was performed using genetic variants as instrumental variables to assess the causal relationship between BMI and RP. A two-step MR method was applied to examine the mediating role of inflammatory factors. Data were derived from summary statistics of multiple genome-wide association studies (GWAS), involving large-scale European populations. The analysis included BMI, RP, and 91 inflammatory factors, with sensitivity analysis to verify the robustness of the findings. Results: A significant positive causal relationship between BMI and RP was identified (IVW OR = 1.419, 95% CI = 1.211~1.664, P < 0.001), and no reverse causal association was detected in the reverse analysis. Further analysis revealed that inflammatory factors IL-2 and VEGF-a mediate the BMI-RP relationship, with mediation effect values of β = 0.025 (proportion 7.24%) and β = 0.014 (proportion 3.86%), respectively. Sensitivity analysis confirmed that the results were robust, with no pleiotropy or heterogeneity interference. Conclusion: BMI influences the onset and progression of RP through chronic inflammation and metabolic dysregulation, with IL-2 and VEGF-a playing crucial mediating roles in this process. This study offers new insights for the prevention and treatment of RP, highlighting the potential for intervention strategies targeting inflammatory pathways.