Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.
Role of Blood Lipids in the Development of Ischemic Stroke and its Subtypes: A Mendelian Randomization Study.
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DOI：
10.1161/strokeaha.117.019653
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发表时间：
2018-04
期刊：
影响因子：
8.3
通讯作者：
Stroke Genetics Network (SiGN)
中科院分区：
文献类型：
--
作者：
Hindy G;Engström G;Larsson SC;Traylor M;Markus HS;Melander O;Orho-Melander M;Stroke Genetics Network (SiGN)
补充数字内容可在文本中找到。他汀类药物治疗与缺血性卒中风险降低相关，支持低密度脂蛋白（LDL）胆固醇的因果作用。然而，需要更多的证据来回答低密度脂蛋白胆固醇是否在缺血性卒中亚型中起因果作用的问题。此外，高密度脂蛋白胆固醇和甘油三酯是否与缺血性卒中及其亚型有因果关系尚不清楚。我们的目的是通过孟德尔随机化（MR）研究低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和甘油三酯在缺血性卒中及其亚型中的因果作用。从全球脂质遗传学联盟和卒中遗传学网络获得了185个全基因组脂质相关单核苷酸多态性的汇总数据，用于研究它们与缺血性卒中（n=16 851例和32 473例对照）及其亚型(包括大动脉粥样硬化（n=2410）、小动脉闭塞（n=3186）和心脏栓塞（n=3427）卒中的关联。使用反方差加权MR来获得因果估计。采用反方差加权多变量MR、MR- egger和敏感性排除Steiger滤波后的多效单核苷酸多态性，并采用MR-多效残差和和离群检验来调整多效偏倚。1-SD遗传升高的低密度脂蛋白胆固醇与缺血性卒中（优势比：1.12；95%可信区间：1.04-1.20）和大动脉粥样硬化卒中（优势比：1.28；95%可信区间：1.10-1.49）的风险增加相关，但与多变量mr中小动脉闭塞或心栓性卒中无关。1-SD遗传升高的高密度脂蛋白胆固醇与小动脉闭塞卒中的风险降低相关(优势比：0.79；95%可信区间：0.67-0.90)，MR-Egger显示没有多效性偏倚，在敏感性排除多效性单核苷酸多态性后，结果没有明显变化。甘油三酯基因升高与缺血性中风或其亚型无关。降低低密度脂蛋白胆固醇可能预防大动脉粥样硬化，但可能不能预防小动脉闭塞或心脏栓塞性中风。高密度脂蛋白胆固醇升高可能有利于小动脉疾病的预防。最后，降低甘油三酯可能不会对缺血性卒中及其亚型产生益处。
Supplemental Digital Content is available in the text. Statin therapy is associated with a lower risk of ischemic stroke supporting a causal role of low-density lipoprotein (LDL) cholesterol. However, more evidence is needed to answer the question whether LDL cholesterol plays a causal role in ischemic stroke subtypes. In addition, it is unknown whether high-density lipoprotein cholesterol and triglycerides have a causal relationship to ischemic stroke and its subtypes. Our aim was to investigate the causal role of LDL cholesterol, high-density lipoprotein cholesterol, and triglycerides in ischemic stroke and its subtypes through Mendelian randomization (MR). Summary data on 185 genome-wide lipids-associated single nucleotide polymorphisms were obtained from the Global Lipids Genetics Consortium and the Stroke Genetics Network for their association with ischemic stroke (n=16 851 cases and 32 473 controls) and its subtypes, including large artery atherosclerosis (n=2410), small artery occlusion (n=3186), and cardioembolic (n=3427) stroke. Inverse-variance–weighted MR was used to obtain the causal estimates. Inverse-variance–weighted multivariable MR, MR-Egger, and sensitivity exclusion of pleiotropic single nucleotide polymorphisms after Steiger filtering and MR-Pleiotropy Residual Sum and Outlier test were used to adjust for pleiotropic bias. A 1-SD genetically elevated LDL cholesterol was associated with an increased risk of ischemic stroke (odds ratio: 1.12; 95% confidence interval: 1.04–1.20) and large artery atherosclerosis stroke (odds ratio: 1.28; 95% confidence interval: 1.10–1.49) but not with small artery occlusion or cardioembolic stroke in multivariable MR. A 1-SD genetically elevated high-density lipoprotein cholesterol was associated with a decreased risk of small artery occlusion stroke (odds ratio: 0.79; 95% confidence interval: 0.67–0.90) in multivariable MR. MR-Egger indicated no pleiotropic bias, and results did not markedly change after sensitivity exclusion of pleiotropic single nucleotide polymorphisms. Genetically elevated triglycerides did not associate with ischemic stroke or its subtypes. LDL cholesterol lowering is likely to prevent large artery atherosclerosis but may not prevent small artery occlusion nor cardioembolic strokes. High-density lipoprotein cholesterol elevation may lead to benefits in small artery disease prevention. Finally, triglyceride lowering may not yield benefits in ischemic stroke and its subtypes.