Department of Neurology, Peking, University Third Hospital, Beijing, China.
Department of Epidemiology & Biostatistics, School of Public Health, Peking University, Beijing, China.
Ann Neurol. 2022 Sep;92(3):390-399. doi: 10.1002/ana.26426. Epub 2022 Jun 24.
To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease.
Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH.
Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH.
Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399.
探讨脂质或载脂蛋白特征在脑出血（ICH）中的因果作用，并确定降脂干预对该疾病的影响。
采用两样本 Mendelian 随机化（MR）分析评估高密度脂蛋白胆固醇、低密度脂蛋白胆固醇（LDL-C）、甘油三酯（TG）、载脂蛋白（Apo）B 和 ApoA1 水平与 ICH 风险的关联，以及 LDL-C 降低靶点（HMGCR、PCSK9 和 NPC1L1）和 TG 降低靶点（LPL 和 APOC3）与 ICH 的关联。
ApoB 水平升高与总体 ICH（OR 0.623，95%CI 0.413-0.940；p=0.024）和皮质下 ICH（OR 0.579，95%CI 0.342-0.979；p=0.042）风险降低相关。多变量 MR 分析结果仍然稳定。此外，升高的 TG 与多变量 MR 皮质下 ICH 有因果关系（OR 1.600，95%CI 1.009-2.537；p=0.046）。位于 HMGCR 基因内或附近的 LDL-C 降低遗传变异等位基因（模拟他汀类药物的作用）被预测会增加总体和深部 ICH 风险。此外，位于 APOC3 基因内或附近的遗传变异表明，遗传降低 APOC3 的活性（模拟反义抗 apoC3 剂）被预测会降低皮质下 ICH。
遗传预测的 ApoB 升高可能对总体 ICH 和皮质下 ICH 具有保护作用，而升高的 TG 与 LDL-C 和 ApoB 条件下皮质下 ICH 的风险增加相关。MR 分析支持他汀类药物可能独立于其降脂作用增加总体和深部 ICH 风险的结论。更具体的降脂靶点可能成为未来的研究方向。
