Chen Haohao, Zheng Zequn, Cai Xiaorui, Li Shunxian, Chen Manli, Wu Jiaming, He Wenzhen, Gao Fenfei
Department of Pharmacy, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
Department of Pharmacy, Shantou University Medical College, Shantou, China.
Front Neurol. 2024 Sep 30;15:1437153. doi: 10.3389/fneur.2024.1437153. eCollection 2024.
Ischemic stroke (IS) is a global health issue linked to lipid metabolism and immune cell responses. This study uses Mendelian randomization (MR) to identify genetic risk factors for IS subtypes using comprehensive genetic data from lipidomic and immune cell profiles.
We assessed genetic susceptibility to IS across 179 lipids and 731 immune cell phenotypes using instrumental variables (IVs) from recent genome-wide association studies. A two-sample MR approach evaluated correlations, and a two-step MR mediation analysis explored the role of immune cell phenotypes in the lipid-IS pathway. Sensitivity analyses, including MR-Egger and Cochran tests, ensured robust results.
Genetic IVs for 162 lipids and 614 immune cell phenotypes were identified. Significant genetic causality was found between 35 lipids and large artery stroke (LAS), with 12 as risk factors (sterol esters, phosphatidylcholines, phosphatidylethanolamines) and 23 as protective factors (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols). For small vessel stroke (SVS), 8 as risk factors (sterol esters, phosphatidylcholines), and 2 as protective factors (phosphatidylinositol, sphingomyelin). For cardioembolic stroke (CS), 2 as risk factors, and 4 as protective factors. Mediation analysis revealed that CCR2 on granulocytes, CD11c on CD62L myeloid dendritic cells, and FSC-A on granulocytes mediated the lipid-immune cell-LAS pathway, while CD4 on activated CD4 regulatory T cells and CD4 on activated & secreting CD4 regulatory T cells mediated the lipid-immune cell-SVS pathway.
This study identifies genetic links between specific lipids and IS subtypes, highlights immune cells' role in IS risk and mediation, suggests new therapeutic targets, and uncovers IS genetic drivers.
缺血性中风（IS）是一个与脂质代谢和免疫细胞反应相关的全球性健康问题。本研究使用孟德尔随机化（MR）方法，利用来自脂质组学和免疫细胞谱的综合遗传数据，确定IS亚型的遗传风险因素。
我们使用近期全基因组关联研究中的工具变量（IVs），评估了179种脂质和731种免疫细胞表型对IS的遗传易感性。采用两样本MR方法评估相关性，并通过两步MR中介分析探讨免疫细胞表型在脂质-IS途径中的作用。敏感性分析，包括MR-Egger和Cochran检验，确保了结果的稳健性。
确定了162种脂质和614种免疫细胞表型的遗传IVs。发现35种脂质与大动脉粥样硬化性卒中（LAS）之间存在显著的遗传因果关系，其中12种为危险因素（甾醇酯、磷脂酰胆碱、磷脂酰乙醇胺），23种为保护因素（磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇）。对于小动脉闭塞性卒中（SVS），8种为危险因素（甾醇酯、磷脂酰胆碱），2种为保护因素（磷脂酰肌醇、鞘磷脂）。对于心源性栓塞性卒中（CS），2种为危险因素，4种为保护因素。中介分析显示，粒细胞上的CCR2、CD62L髓样树突状细胞上的CD11c以及粒细胞上的FSC-A介导了脂质-免疫细胞-LAS途径，而活化的CD4调节性T细胞上的CD4和活化并分泌的CD4调节性T细胞上的CD4介导了脂质-免疫细胞-SVS途径。
本研究确定了特定脂质与IS亚型之间的遗传联系，突出了免疫细胞在IS风险和中介作用中的作用，提出了新的治疗靶点，并揭示了IS的遗传驱动因素。
