脂质代谢组与卒中的因果关系：系统孟德尔随机化研究

doi:10.3969/j.issn.1673-5765.2025.06.003

摘要/Abstract

摘要： 目的脂质代谢异常与卒中的发生发展密切相关。本研究旨在探究脂质代谢组与卒中及其亚型的因果关联，解析脂蛋白成分对卒中的影响。
方法基于213种脂质代谢指标以及全因卒中（any stroke，AS）、全因缺血性卒中（any ischemic stroke，AIS）及其3种亚型——大动脉型卒中（large artery stroke，LAS）、心源性栓塞型卒中（cardioembolic stroke，CES）和小血管型卒中（small vessel stroke，SVS）的GWAS，通过单变量孟德尔随机化（Mendelian randomization，MR）方法初步筛选与卒中存在潜在因果关系的脂质代谢指标。在此基础上，运用多变量MR方法整合脂质代谢指标间的遗传相关性，进一步鉴定具有独立因果效应的脂质代谢指标。
结果在单变量MR中，分别识别出16种、58种和58种脂质代谢指标与AS、AIS及LAS存在潜在因果关联，仅各发现1种与CES和SVS相关的脂质代谢指标。这些脂质代谢指标间普遍存在遗传相关性。通过多变量MR的进一步筛选，分别识别出11种、4种和39种与AS、AIS及LAS相关的高置信度脂质代谢指标。其中，小颗粒低密度脂蛋白（small-low density lipoprotein，S-LDL）及中颗粒低密度脂蛋白（medium-low density lipoprotein，M-LDL）和小颗粒高密度脂蛋白中的磷脂与总脂质的比值，对卒中及其亚型具有潜在保护效应；而S-LDL和M-LDL中的胆固醇、胆固醇酯等脂质成分，则与LAS发病风险升高相关。
结论脂质代谢指标对LAS的影响最为显著，脂蛋白颗粒中的胆固醇和磷脂占比在卒中发生发展中发挥差异化作用。

文章导读： 本研究通过单变量和多变量孟德尔随机化分析，揭示了脂质代谢组与卒中及其亚型之间的因果关系，小/中颗粒低密度脂蛋白及小颗粒高密度脂蛋白中的磷脂与总脂质的比值，对卒中及其亚型具有潜在保护效应。

关键词: 脂质代谢组; 卒中; 孟德尔随机化; 因果关联

Abstract: Objective Abnormal lipid metabolism is closely associated with the occurrence and development of stroke. This study aims to explore the causal associations between lipid metabolome and stroke as well as its subtypes, and to analyze the impact of lipoprotein components on stroke.
Methods Based on the GWAS of 213 lipid metabolites, as well as any stroke (AS), any ischemic stroke (AIS), and its three subtypes—large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS), univariate Mendelian randomization (MR) methods were used to screen the lipid metabolites that have potential causal relationships with stroke. On this basis, multivariate MR methods were employed to integrate the genetic correlations among lipid metabolites, further identifying those with independent causal effects.
Results In the univariate MR analysis, 16, 58, and 58 lipid metabolites were identified as having potential causal associations with AS, AIS, and LAS, respectively, while only one lipid metabolite was found to be associated with each of CES and SVS. There were widespread genetic correlations among these lipid metabolites. Through further screening by multivariate MR analysis, 11, 4, and 39 lipid metabolites with high-confidence associations with AS, AIS, and LAS were identified, respectively. Among them, small-low density lipoprotein (S-LDL), medium-low density lipoprotein (M-LDL), and the ratio of phospholipids to total lipids in small-high density lipoproteins had potential protective effects on stroke and its subtypes; while lipid components such as cholesterol and cholesterol esters in S-LDL and M-LDL were significantly associated with an increased risk of LAS.
Conclusions Lipid metabolites exert the most significant effect on LAS, and the proportion of cholesterol and phospholipids in lipoprotein particles plays differentiated roles in the occurrence and development of stroke.

Key words: Lipid metabolome; Stroke; Mendelian randomization; Causal association

中图分类号:

姜明慧, 许喆, 石延枫, 张杰, 李昊, 程丝. 脂质代谢组与卒中的因果关系：系统孟德尔随机化研究[J]. 中国卒中杂志, 2025, 20(6): 675-685.

JIANG Minghui, XU Zhe, SHI Yanfeng, ZHANG Jie, LI Hao, CHENG Si. Causal Relationship between Lipid Metabolome and Stroke: A Systematic Mendelian Randomization Study[J]. Chinese Journal of Stroke, 2025, 20(6): 675-685.

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