广西医学

目的基于双向孟德尔随机化（MR）分析法探讨血细胞扰动反应与血管性痴呆（VAD）之间的因果关系。方法从FinnGen数据库中获取血细胞扰动反应和VAD的全基因组关联研究数据，以血细胞扰动反应和VAD互为暴露因素和结局，以与暴露因素相关的单核苷酸多态性（SNP）为工具变量。筛选工具变量后，使用逆方差加权（IVW）法作为MR分析的主要方法，以MR Egger法、加权中位数法、简单模式法和加权模式法作为补充方法，进行双向MR分析。使用Cochran's Q检验评估异质性，通过MR Egger法的截距项和MR⁃PRESSO法评估水平多效性，采用留一法评估结果稳定性。结果正向MR分析中，IVW法分析结果显示，中性粒细胞扰动反应［OR=1.088（95% CI：1.018，1.163），P=0.013］和单核细胞扰动反应［OR=1.038（95% CI：1.001，1.076），P=0.044］与VAD的发生呈正相关，其他分析方法的结果在关联性方向上亦基本一致；血小板扰动反应与VAD的发生呈负相关［OR=0.923（95% CI：0.874，0.974），P=0.004］，其他分析方法的结果在关联性方向上一致。反向MR分析中，IVW法分析结果显示，VAD与白细胞扰动反应［OR=1.154（95% CI：1.020，1.306），P=0.023］和红细胞扰动反应［OR=1.215（95% CI：1.034，1.428），P=0.018］呈正相关，其他分析方法的结果在关联性方向上亦基本一致。双向MR分析中，Cochran's Q检验结果均提示各SNP之间不存在异质性（P>0.05）。漏斗图结果也显示，各效应量点分布基本对称。MR Egger法的截距及MR⁃PRESSO法分析结果显示本研究不存在水平多效性（P>0.05）。留一法检验结果显示因果关系稳定可靠。结论中性粒细胞扰动反应和单核细胞扰动反应会增加VAD的发生风险，而血小板扰动反应对VAD具有保护作用。反之，VAD的发生会加剧白细胞扰动反应和红细胞扰动反应。

Objective To explore the causality of blood cell perturbation response with vascular dementia (VAD) based on bidirectional Mendelian randomization (MR) analytic method. Methods Blood cell perturbation response and Genome⁃wide Association Study data of VAD were retrieved from the database of FinnGen. Blood cell perturbation response and VAD were mutually exposed factors and outcome, and single nucleotide polymorphisms (SNP) related to exposed factors were used as instrumental variables. After screening the instrumental variables, inverse variance weighted method was adopted to be the main method of MR analysis, and bidirectional MR analysis was performed by using MR Egger, weighted median method, simple mode, and weighted mode as supplements. Cochran's Q test was explored to evaluate heterogeneity, intercept term was observed through MR Egger method, horizontal pleiotropy was evaluated by MR⁃PRESSO, and result stability was conducted using leave⁃one⁃out method. Results In the forward MR analysis, results of IVW analysis indicated that neutrophil perturbation response (OR=1.088 ［95% CI: 1.018, 1.163］, P=0.013) and monocyte perturbation response (OR=1.038 ［95% CI: 1.001, 1.076］, P=0.044) positively correlated with the occurrence of VAD, with results from the remaining analytical methods largely consistent in direction. Platelet perturbation response negatively correlated with the occurrence of VAD (OR=0.923 ［95% CI: 0.874, 0.974］, P=0.004), and results from the remaining analytical methods were consistent in direction. In the reverse MR analysis, results of IVW analysis revealed that VAD positively correlated with leukocyte perturbation response (OR=1.154 ［95% CI: 1.020, 1.306］, P=0.023) and erythrocyte perturbation response (OR=1.215 ［95% CI: 1.034, 1.428］, P=0.018), with results from the remaining analytical methods also largely consistent in direction. In the bidirectional MR analysis, Cochran's Q test results suggested no heterogeneity between SNP (P>0.05). Funnel plot results also expressed that the distribution of effect size was generally symmetrical. MR Egger intercept tests and MR⁃PRESSO analysis results indicated no horizontal pleiotropy in this study (P>0.05). Leave⁃one⁃out analysis demonstrated stable and reliable causality. Conclusion Neutrophil perturbation response and monocyte perturbation response will increase occurrence risk of VAD, whereas platelet perturbation response exerts protective effect on VAD. Conversely, the occurrence of VAD will intensify leukocyte perturbation response and erythrocyte perturbation response.