Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden.
Ann Neurol. 2020 Dec;88(6):1229-1236. doi: 10.1002/ana.25916. Epub 2020 Oct 10.
We conducted a Mendelian randomization (MR) study to disentangle the comparative effects of lipids and apolipoproteins on ischemic stroke.
Single-nucleotide polymorphisms associated with low- and high-density lipoprotein (LDL and HDL) cholesterol, triglycerides, and apolipoprotein A-I and B (apoA-I and apoB) at the level of genomewide significance (p < 5 × 10 ) in the UK Biobank were used as instrumental variables. Summary-level data for ischemic stroke and its subtypes were obtained from the MEGASTROKE consortium with 514,791 individuals (60,341 ischemic stroke cases, and 454,450 non-cases).
Increased levels of apoB, LDL cholesterol, and triglycerides were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke in the main and sensitivity univariable MR analyses. In multivariable MR analysis including apoB, LDL cholesterol, and triglycerides in the same model, apoB retained a robust effect (p < 0.05), whereas the estimate for LDL cholesterol was reversed, and that for triglycerides largely attenuated. Decreased levels of apoA-I and HDL cholesterol were robustly associated with increased risk of any ischemic stroke, large artery stroke, and small vessel stroke in all univariable MR analyses, but the association for apoA-I was attenuated to the null after mutual adjustment.
The present MR study reveals that apoB is the predominant trait that accounts for the etiological basis of apoB, LDL cholesterol, and triglycerides in relation to ischemic stroke, in particular large artery and small vessel stroke. Whether HDL cholesterol exerts a protective effect on ischemic stroke independent of apoA-I needs further investigation. ANN NEUROL 2020;88:1229-1236.
我们进行了一项孟德尔随机化（MR）研究，以厘清脂质和载脂蛋白对缺血性卒中的相对影响。
采用全基因组关联研究中具有统计学显著意义（p<5×10）的与低、高密度脂蛋白（LDL 和 HDL）胆固醇、甘油三酯以及载脂蛋白 A-I 和 B（apoA-I 和 apoB）相关的单核苷酸多态性作为工具变量。利用 MEGASTROKE 联盟获得的缺血性卒中及其亚型的汇总水平数据，该研究共纳入 514791 名个体（60341 例缺血性卒中病例，454450 例非病例）。
在主要和敏感性单变量 MR 分析中，apoB、LDL 胆固醇和甘油三酯水平升高与任何缺血性卒中、大动脉卒中和小血管卒中等风险增加相关。在包括 apoB、LDL 胆固醇和甘油三酯于同一模型的多变量 MR 分析中，apoB 仍保留着显著的作用（p<0.05），而 LDL 胆固醇的估计值则相反，甘油三酯的估计值则大大减弱。apoA-I 和 HDL 胆固醇水平降低与任何缺血性卒中、大动脉卒中和小血管卒中等风险增加显著相关，在所有单变量 MR 分析中均如此，但在相互调整后，apoA-I 的相关性减弱至无统计学意义。
本 MR 研究揭示，apoB 是解释 apoB、LDL 胆固醇和甘油三酯与缺血性卒中之间因果关系的主要特征，特别是大动脉卒中和小血管卒中等。HDL 胆固醇是否独立于 apoA-I 对缺血性卒中发挥保护作用仍需进一步研究。
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