Division of Neurocritical Care & Emergency Neurology, Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
Center for Genomic Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
Ann Neurol. 2020 Jul;88(1):56-66. doi: 10.1002/ana.25740. Epub 2020 May 7.
Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH.
We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses.
We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively.
Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.
观察性研究表明，低密度脂蛋白（LDL）胆固醇水平与脑出血（ICH）风险呈负相关，但尚不清楚这种关联是否具有因果关系。我们检验了这样一种假设，即遗传上升高的 LDL 与降低 ICH 风险有关。
我们使用每个脂质特征（总胆固醇、LDL、高密度脂蛋白[HDL]和甘油三酯）的独立全基因组显著单核苷酸多态性（SNP）构建了一个多基因风险评分（PRS）。我们使用来自英国生物库的 316428 名参与者的数据来估计每个 PRS 对其相应特征的影响，以及来自 1286 例 ICH 病例和 1261 例匹配对照的影响来估计每个 PRS 对 ICH 风险的影响。我们使用这些估计值进行了孟德尔随机化（MR）分析。
我们分别确定了总胆固醇、LDL、HDL 和甘油三酯的 410、339、393 和 317 个脂质相关 SNP。所有四个 PRS 与相应的特征均呈强相关（均 p <1.00×10）。总胆固醇（OR=0.92；95%置信区间[CI]为 0.85-0.99；p=0.03）和 LDL 胆固醇（OR=0.88；95%CI 为 0.81-0.95；p=0.002）的 PRS 每增加一个标准差与 ICH 风险呈负相关，而 HDL 和甘油三酯则无显著相关性（均 p >0.05）。MR 分析表明，遗传上增加 1mmol/L（38.67mg/dL）的总胆固醇和 LDL 胆固醇与 ICH 风险降低 23%（OR=0.77；95%CI 为 0.65-0.98；p=0.03）和 41%（OR=0.59；95%CI 为 0.42-0.82；p=0.002）相关。
遗传上升高的 LDL 水平与 ICH 风险降低有关，为 LDL 胆固醇在 ICH 中的潜在因果作用提供了支持。
