Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, Guangzhou, Guangdong, China.
Guangdong-Hong Kong Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China, Guangzhou, Guangdong, China.
Front Immunol. 2024 May 30;15:1389843. doi: 10.3389/fimmu.2024.1389843. eCollection 2024.
Preeclampsia/eclampsia (PE), a critical complication during pregnancy, has been suggested to correlate with immune cell phenotypes and levels of circulating inflammatory proteins. Our study aimed to employ a two-sample mendelian randomization (MR) analysis to assess the potential causal effects of immune cell phenotypes and circulating inflammatory proteins on the onset of PE.
We utilized summary-level data from genome-wide association studies (GWAS). This included statistics for 371 immune cell phenotypes from 3,757 individuals in the Sardinian founder population, and data on 91 circulating inflammatory proteins from 14,824 European ancestry participants. Additionally, genetic associations related to PE were extracted from the FinnGen consortium, involving 1,413 cases and 287,137 controls. We applied inverse variance weighting (IVW) and supplementary methods like MR-Egger, weighted median, and weighted mode to comprehensively assess potential causal links.
Our analysis revealed significant causal associations of several immune cells type and inflammatory proteins with PE. Out of the immune cell phenotypes analyzed, six immune phenotypes emerged as significant risk factors (0.01), mainly include CD4 on activated and secreting CD4 regulatory T cells, CD28 on CD39+ CD4+ T cells, CD127- CD8+ T cell absolute cell (AC) counts, HLA DR on HLA DR+ CD8+ T cell, CD66b on CD66b++ myeloid cells, and HLA DR on dendritic cells. And ten were identified as protective factors (0.01). Such as CD45 on CD33br HLA DR+ CD14-, CD33+ HLA DR+ AC, CD33+ HLA DR+ CD14- AC, CD33+ HLA DR+ CD14dim AC, CD27 on CD24+ CD27+ B cell, CD20- CD38- %B cell, IgD- CD24- %B cell CD80 on plasmacytoid DC, CD25 on CD4+ T cell, and CD25 on activated & secreting CD4 regulatory T cell. Furthermore, among the inflammatory proteins studied, five showed a significant association with PE, with three offering protective effects mainly include that C-X-C motif chemokine 1, tumor necrosis factor ligand superfamily member 14, and C-C motif chemokine 19 and two exacerbating PE risk such as STAM-binding domain and Interleukin-6 (p <0.05).
Our study highlights the pivotal roles played by diverse immune cell phenotypes and circulating inflammatory proteins in the pathophysiology of PE. These findings illuminate the underlying genetic mechanisms, emphasizing the criticality of immune regulation during pregnancy. Such insights could pave the way for novel intervention strategies in managing PE, potentially enhancing maternal and neonatal health outcomes.
子痫前期/子痫（PE）是妊娠期间的一种严重并发症，据报道与免疫细胞表型和循环炎症蛋白水平有关。本研究旨在采用两样本孟德尔随机化（MR）分析来评估免疫细胞表型和循环炎症蛋白对 PE 发病的潜在因果影响。
我们利用全基因组关联研究（GWAS）的汇总数据。这包括来自撒丁岛创始人群 3757 名个体的 371 种免疫细胞表型的统计数据，以及来自 14824 名欧洲血统参与者的 91 种循环炎症蛋白的数据。此外，从 FinnGen 联盟提取了与 PE 相关的遗传关联，涉及 1413 例病例和 287137 例对照。我们应用逆方差加权（IVW）和补充方法（如 MR-Egger、加权中位数和加权模式）全面评估潜在的因果关系。
我们的分析显示，几种免疫细胞类型和炎症蛋白与 PE 有显著的因果关联。在分析的免疫细胞表型中，六种免疫表型被确定为显著的风险因素（0.01），主要包括激活和分泌 CD4 的 CD4 调节性 T 细胞上的 CD28、CD39+CD4+T 细胞上的 CD127-CD8+T 细胞绝对细胞（AC）计数、HLA-DR+CD8+T 细胞上的 HLA-DR、CD66b++髓样细胞上的 CD66b 和树突状细胞上的 HLA-DR。十种被确定为保护因素（0.01）。例如 CD33brHLA-DR+CD14-CD33+ HLA-DR+AC、CD33+HLA-DR+CD14-AC、CD33+HLA-DR+CD14dimAC、CD27+CD24+CD27+B 细胞上的 CD27、CD20-CD38-%B 细胞、浆细胞样树突状细胞上的 CD80、CD4+T 细胞上的 CD25 和激活和分泌 CD4 调节性 T 细胞上的 CD25。此外，在所研究的炎症蛋白中，五种与 PE 有显著关联，其中三种提供保护作用，主要包括 C-X-C 基序趋化因子 1、肿瘤坏死因子配体超家族成员 14 和 C-C 基序趋化因子 19，两种加剧 PE 风险，如 STAM 结合域和白细胞介素 6（p<0.05）。
本研究强调了不同免疫细胞表型和循环炎症蛋白在 PE 病理生理学中的关键作用。这些发现阐明了潜在的遗传机制，强调了妊娠期间免疫调节的重要性。这些见解为管理 PE 的新干预策略铺平了道路，可能改善母婴健康结局。
