免疫细胞表型与子痫前期的因果关联：一项两样本孟德尔随机化的研究

Causal Association between Immune Cell Phenotypes and Preeclampsia: A Two-Sample Mendelian Randomization Study

摘要: 背景：子痫前期(Preeclampsia, PE)是导致孕产妇及围产儿死亡的主要原因之一，其病理机制尚未完全阐明。越来越多的证据表明，免疫系统失调在其发病过程中扮演着关键角色，但免疫细胞表型与PE之间是否存在确切的因果关系尚不清楚。方法：本研究采用两样本孟德尔随机化分析(Mendelian Randomization, MR)，系统探究731种免疫细胞表型(包括中位荧光强度、相对计数和绝对计数)与PE之间的因果关系。工具变量(Instrumental Variables, IVs)选自大规模免疫细胞特征全基因组关联研究(Genome-Wide Association Studies, GWAS)。主要分析采用逆方差加权法(Inverse Variance Weighted, IVW)，并通过加权中位数法、MR-Egger回归等多种方法进行敏感性分析以评估结果的稳健性。结果：两样本MR分析共发现6种免疫细胞表型与PE风险存在显著因果关联。其中，3种表型为风险因素，包括HLA DR+ NK细胞相对计数(OR = 1.101, 95% CI: 1.027~1.180)、CD14+CD16−单核细胞上CD16的表达水平(OR = 1.113, 95% CI: 1.042~1.189)及CD14−CD16+单核细胞上PD-L1的表达水平(OR = 1.107, 95% CI: 1.027~1.194)。另外3种表型为保护因素，包括CD62L−髓系树突状细胞占比(OR = 0.931, 95% CI: 0.887~0.977)、CD62L−CD86+髓系树突状细胞占比(OR = 0.921, 95% CI: 0.869~0.976)及粒细胞的侧向散射强度(OR = 0.912, 95% CI: 0.851~0.978)。结论：本研究通过遗传学证据揭示了特定的免疫细胞表型是PE发病的因果风险因素。这些发现为理解子痫前期的免疫病理机制提供了新的见解，并提示相关免疫细胞通路或可作为未来预防和干预的潜在靶点。

Abstract: Background: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality, and its pathological mechanisms remain incompletely understood. Growing evidence suggests that immune system dysregulation plays a key role in its pathogenesis. However, whether a definitive causal relationship exists between immune cell phenotypes and PE is still unclear. Methods: This study employed two-sample Mendelian Randomization (MR) analysis to systematically investigate the causal relationships between 731 immune cell phenotypes (including median fluorescence intensity, relative count, and absolute count) and PE. Instrumental Variables (IVs) were selected from large-scale Genome-Wide Association Studies (GWAS) on immune cell characteristics. The primary analysis utilized the Inverse Variance Weighted (IVW) method, supplemented by sensitivity analyses, including the weighted median method and MR-Egger regression, to evaluate the robustness of the findings. Results: The two-sample MR analysis identified six immune cell phenotypes with significant causal associations with PE risk. Among them, three phenotypes were identified as risk factors: HLA DR+ NK cell relative count (OR = 1.101, 95% CI: 1.027~1.180), CD16 expression level on CD14+CD16− monocytes (OR = 1.113, 95% CI: 1.042~1.189), and PD-L1 expression level on CD14−CD16+ monocytes (OR = 1.107, 95% CI: 1.027~1.194). The other three phenotypes were protective factors: CD62L− myeloid dendritic cell proportion (OR = 0.931, 95% CI: 0.887~0.977), CD62L−CD86+ myeloid dendritic cell proportion (OR = 0.921, 95% CI: 0.869~0.976), and side scatter intensity of granulocytes (OR = 0.912, 95% CI: 0.851~0.978). Conclusion: This study provides genetic evidence suggesting that specific immune cell phenotypes are causal risk factors for the development of PE. These findings offer new insights into the immunopathological mechanisms of preeclampsia and suggest that relevant immune cell pathways may serve as potential targets for future prevention and intervention.