Li Qi, Shen Yingjie, Yu Zhao, Wang Yaolou, Shen Yongze, Guo Chunmei, Gao Shang, Yang Hongge, Gao Aili, Liang Hongsheng
NHC Key Laboratory of Cell Transplantation, Department of Neurosurgery; The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, PR China.
School of Life Science, Northeast Agricultural University, Harbin, Heilongjiang Province, PR China.
Curr Neurovasc Res. 2025 Aug 11. doi: 10.2174/0115672026373219250730071202.
Hemorrhagic stroke is a severe disease that endangers human life and well-being, with unclear pathogenesis. Recent studies have found an association between the immune system and hemorrhagic stroke, but the causal relationship between them remains unclear. We aim to elucidate the causal relationships between immune cell traits and hemorrhagic stroke using Mendelian randomization (MR).
We collected genome-wide association studies (GWAS) summary statistics for 731 immune cell traits as exposures, and GWAS data for hemorrhagic stroke outcomes, including intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and cerebral aneurysm (non-ruptured) (CA), from the FinnGen Consortium's R10 dataset. Five methods were employed to evaluate the causal relationships, with the primary method being the inverse-variance weighted (IVW) method. Sensitivity analyses were carried out to enhance the robustness. Subsequently, we performed multivariate MR analyses, including confounding variables. Additionally, reverse MR analyses were carried out. Ultimately, we conducted pathway and functional enrichment analyses.
After univariate and multivariate MR analyses, we identified that the higher counts of herpesvirus entry mediator (HVEM) on effector memory (EM) CD4+ cells (OR=0.954, 95%- CI:0.925-0.984, P=0.003, PFDR=0.120) were a protective factor for SAH, and the counts of forward scatter area (FSC-A) on plasmacytoid dendritic cells (DC) (OR=1.059, 95%CI:1.023-1.095, P=0.001, PFDR=0.066) were associated with an increased risk of CA. The reverse MR indicated that CA could significantly increase the effector memory (EM) DN (CD4-CD8-) AC counts. No significant pleiotropy or heterogeneity was calculated in the MR analyses. SNP annotation and enrichment analyses suggested possible mechanisms by which immune cells affect hemorrhagic stroke.
The involvement of immune cells in the neuroinflammatory responses has been demonstrated in previous studies. Among the immune cell traits with a significant causal relationship to hemorrhagic stroke, higher levels of HVEM on EM CD4+ cells may inhibit further inflammatory progress by binding to corresponding receptors, thereby exerting a protective effect against SAH. Alterations in FSC-A values (a flow cytometry measure of cell size) of plasmacytoid dendritic cells may contribute to atherosclerosis through cascading reactions that ultimately lead to CA. In addition, based on existing studies, other immune cell traits and related pathways identified in this study may contribute to the prevention and treatment of hemorrhagic stroke, providing a reference for future research. Finally, this study has some limitations, including population specificity, the use of a relatively lenient significance threshold (P < 1 × 10-5), and potential bias from weak instrumental variables and pleiotropy.
This study demonstrated the causal relationships between immune cell traits and hemorrhagic stroke, laying the foundation for understanding the underlying mechanisms.
出血性中风是一种危及人类生命健康的严重疾病，其发病机制尚不清楚。最近的研究发现免疫系统与出血性中风之间存在关联，但它们之间的因果关系仍不明确。我们旨在利用孟德尔随机化（MR）阐明免疫细胞特征与出血性中风之间的因果关系。
我们收集了731种免疫细胞特征作为暴露因素的全基因组关联研究（GWAS）汇总统计数据，以及来自芬兰基因组联盟R10数据集的出血性中风结局的GWAS数据，包括脑出血（ICH）、蛛网膜下腔出血（SAH）和脑动脉瘤（未破裂）（CA）。采用五种方法评估因果关系，主要方法为逆方差加权（IVW）法。进行敏感性分析以增强稳健性。随后，我们进行了多变量MR分析，包括混杂变量。此外，还进行了反向MR分析。最后，我们进行了通路和功能富集分析。
经过单变量和多变量MR分析，我们发现效应记忆（EM）CD4+细胞上疱疹病毒进入介质（HVEM）计数较高（OR = 0.954，95%置信区间：0.925 - 0.984，P = 0.003，PFDR = 0.120）是SAH的保护因素，浆细胞样树突状细胞（DC）上的前向散射面积（FSC - A）计数（OR = 1.059，95%置信区间：1.023 - 1.095，P = 0.001，PFDR = 0.066）与CA风险增加相关。反向MR表明CA可显著增加效应记忆（EM）DN（CD4 - CD8 -）AC计数。MR分析中未计算出显著的多效性或异质性。SNP注释和富集分析提示了免疫细胞影响出血性中风的可能机制。
先前的研究已证明免疫细胞参与神经炎症反应。在与出血性中风存在显著因果关系的免疫细胞特征中，EM CD4+细胞上较高水平的HVEM可能通过与相应受体结合抑制进一步的炎症进展，从而对SAH发挥保护作用。浆细胞样树突状细胞FSC - A值（流式细胞术测量的细胞大小）的改变可能通过级联反应导致动脉粥样硬化，最终导致CA。此外，基于现有研究，本研究中确定的其他免疫细胞特征和相关通路可能有助于出血性中风的预防和治疗，为未来研究提供参考。最后，本研究存在一些局限性，包括人群特异性、使用相对宽松的显著性阈值（P < 1×10 - 5）以及弱工具变量和多效性可能导致的潜在偏差。
本研究证明了免疫细胞特征与出血性中风之间的因果关系，为理解其潜在机制奠定了基础。
