Lin Shaochong, Tian Xiangming, Kong Sijia, Zhang Bolun, Wang Sidong, Zhu Kongfu, Liu Xiaomin, Yeung William S B, Cao Dandan, Yao Yuanqing
School of Medicine, Nankai University, Tianjin, People's Republic of China.
Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen, People's Republic of China.
Int J Womens Health. 2025 Mar 17;17:793-806. doi: 10.2147/IJWH.S501620. eCollection 2025.
This study aims to investigate the causal relationship between inflammatory cytokines, immune cells and spontaneous abortion (SA).
A bidirectional two-sample Mendelian randomization (MR) analyses was conducted based on the genetic data of 91 inflammatory cytokines (n=14,824), 731 immune traits (n=3757) and SA (18,680 cases and 162,987 controls) cohorts. Five different MR analysis methods and Bayesian-weighted Mendelian randomization (BWMR) analysis were employed to assess the genetic causal connection. In addition, the robustness of this study results was ensured through comprehensive sensitivity analyses assessing heterogeneity, and potential horizontal pleiotropy and reverse causality.
These MR results suggest that higher levels of two inflammatory cytokines and ten immune cells are associated with a lower risk of SA (OR < 1.00). In contrast, fifteen immune cell traits exhibit a positive relationship with SA risk (OR > 1.00). Notably, mediation analysis revealed that the causal effect of programmed death ligand 1 (PDL1) on SA was partially mediated by CD45 expression on Granulocytic Myeloid-Derived Suppressor Cells (GR-MDSCs), and Terminally Differentiated CD4⁻CD8⁻ T cells also acted as mediators in the causal effect of tumor necrosis factor-beta (TNF-β) on SA.
This study comprehensively assessed the causal relationship between immune-related exposures and SA, identifying several immune factors associated with SA risk. These finding have implications for clinical guidance in pregnancy preparation.
本研究旨在探讨炎性细胞因子、免疫细胞与自然流产（SA）之间的因果关系。
基于91种炎性细胞因子（n = 14824）、731种免疫性状（n = 3757）以及SA（18680例病例和162987例对照）队列的遗传数据进行双向两样本孟德尔随机化（MR）分析。采用五种不同的MR分析方法和贝叶斯加权孟德尔随机化（BWMR）分析来评估遗传因果联系。此外，通过评估异质性、潜在水平多效性和反向因果关系的综合敏感性分析，确保了本研究结果的稳健性。
这些MR结果表明，两种炎性细胞因子和十种免疫细胞水平较高与SA风险较低相关（OR < 1.00）。相比之下，十五种免疫细胞性状与SA风险呈正相关（OR > 1.00）。值得注意的是，中介分析显示，程序性死亡配体1（PDL1）对SA的因果效应部分由粒细胞髓源性抑制细胞（GR - MDSCs）上的CD45表达介导，终末分化的CD4⁻CD8⁻ T细胞在肿瘤坏死因子 - β（TNF - β）对SA的因果效应中也起中介作用。
本研究全面评估了免疫相关暴露与SA之间的因果关系，确定了几种与SA风险相关的免疫因素。这些发现对妊娠准备的临床指导具有重要意义。
