Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation
Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled Mendelian randomization investigation
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血脂和心血管疾病结果的遗传决定因素：广角孟德尔随机化研究
DOI：
10.1101/668970
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Allara E
中科院分区：
文献类型：
--
作者：
Allara E
背景来自随机试验的证据表明，降低LDL（低密度脂蛋白）胆固醇和甘油三酯的治疗可降低冠状动脉疾病（CAD）风险。然而，它们对其他心血管结局的影响仍存在不确定性。因此，我们进行了一个系统的调查循环脂质和心血管结局之间的因果关系，使用孟德尔随机化approach.MethodsIn主要分析，我们进行了2样本多变量孟德尔随机化使用的数据来自欧洲血统的参与者。我们还使用逆方差加权和稳健方法进行了单变量分析，并使用可被视为特定降脂药物代理的变体进行了基因特异性分析。我们从全球脂质遗传学联盟获得了与脂质组分的相关性，这是一项对188 577名参与者的荟萃分析，并从英国生物库的367 703名参与者中获得了与心血管结局的遗传相关性。（每增加1个SD的比值比[OR]，1.45 [95% CI，1.35-1.57]）和其他动脉粥样硬化结局（缺血性脑血管疾病和外周血管疾病），我们发现遗传预测的低密度脂蛋白胆固醇与腹主动脉瘤的独立关联（OR，1.75 [95% CI，1.40-2.17]）和主动脉瓣狭窄（OR，1.46 [95% CI，1.25-1.70]）。遗传学预测的甘油三酯水平与CAD呈正相关（OR，1.25 [95% CI，1.12-1.40]），主动脉瓣狭窄（OR，1.29 [95% CI，1.04-1.61]），和高血压（OR，1.17 [95% CI，1.07-1.27]），但与静脉血栓栓塞（OR，0.79 [95% CI，0.67-0.93]）和出血性卒中（OR，0.78 [95% CI，0.62-0.98]）呈负相关。我们还发现，积极的关联，基因预测的LDL-胆固醇和甘油三酯与心力衰竭，似乎是介导的CAD.ConclusionsLowering LDL-胆固醇是可能的，以防止腹主动脉瘤和主动脉瓣狭窄，除了CAD和其他动脉粥样硬化性心血管疾病的结果。降低甘油三酯可能预防CAD和主动脉瓣狭窄，但可能增加血栓栓塞风险。
BackgroundEvidence from randomized trials has shown that therapies that lower LDL (low-density lipoprotein)-cholesterol and triglycerides reduce coronary artery disease (CAD) risk. However, there is still uncertainty about their effects on other cardiovascular outcomes. We therefore performed a systematic investigation of causal relationships between circulating lipids and cardiovascular outcomes using a Mendelian randomization approach.MethodsIn the primary analysis, we performed 2-sample multivariable Mendelian randomization using data from participants of European ancestry. We also conducted univariable analyses using inverse-variance weighted and robust methods, and gene-specific analyses using variants that can be considered as proxies for specific lipid-lowering medications. We obtained associations with lipid fractions from the Global Lipids Genetics Consortium, a meta-analysis of 188 577 participants, and genetic associations with cardiovascular outcomes from 367 703 participants in UK Biobank.ResultsFor LDL-cholesterol, in addition to the expected positive associations with CAD risk (odds ratio [OR] per 1 SD increase, 1.45 [95% CI, 1.35–1.57]) and other atheromatous outcomes (ischemic cerebrovascular disease and peripheral vascular disease), we found independent associations of genetically predicted LDL-cholesterol with abdominal aortic aneurysm (OR, 1.75 [95% CI, 1.40–2.17]) and aortic valve stenosis (OR, 1.46 [95% CI, 1.25–1.70]). Genetically predicted triglyceride levels were positively associated with CAD (OR, 1.25 [95% CI, 1.12–1.40]), aortic valve stenosis (OR, 1.29 [95% CI, 1.04–1.61]), and hypertension (OR, 1.17 [95% CI, 1.07–1.27]), but inversely associated with venous thromboembolism (OR, 0.79 [95% CI, 0.67–0.93]) and hemorrhagic stroke (OR, 0.78 [95% CI, 0.62–0.98]). We also found positive associations of genetically predicted LDL-cholesterol and triglycerides with heart failure that appeared to be mediated by CAD.ConclusionsLowering LDL-cholesterol is likely to prevent abdominal aortic aneurysm and aortic stenosis, in addition to CAD and other atheromatous cardiovascular outcomes. Lowering triglycerides is likely to prevent CAD and aortic valve stenosis but may increase thromboembolic risk.