Abstract Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

中文翻译：

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低密度脂蛋白会导致动脉粥样硬化性心血管疾病。1. 来自遗传、流行病学和临床研究的证据。欧洲动脉粥样硬化学会共识小组的共识声明

摘要 目的评价低密度脂蛋白（LDLs）引起动脉粥样硬化性心血管疾病（ASCVD）的临床和遗传学证据。方法和结果 我们通过评估遗传研究、前瞻性流行病学队列研究、孟德尔随机化研究和降低 LDL 疗法的随机试验的全部证据来评估 LDL 和 ASCVD 之间的关联是否符合因果关系标准。在临床研究中，血浆 LDL 负荷通常通过测定血浆 LDL 胆固醇水平 (LDL-C) 来估计。导致 LDL 受体功能降低的罕见基因突变导致 LDL-C 显着升高和 ASCVD 风险的剂量依赖性增加，而导致 LDL-C 降低的罕见基因突变与 ASCVD 风险相应降低相关。对 200 多项前瞻性队列研究、孟德尔随机研究和随机试验（包括超过 200 万参与者、超过 2000 万人年的随访和超过 150 000 起心血管事件）的单独荟萃分析显示出非常一致的剂量依赖性 log-血管系统暴露于 LDL-C 的绝对量与 ASCVD 风险之间的线性关系；并且这种影响似乎随着暴露于 LDL-C 的持续时间的增加而增加。自然随机遗传研究和随机干预试验都一致表明，降低血浆 LDL 颗粒浓度的任何机制都应降低 ASCVD 事件的风险，这与 LDL-C 的绝对降低和暴露于较低 LDL-C 的累积持续时间成正比，前提是 LDL-C 的降低与 LDL 颗粒数量的降低一致，并且不存在竞争性的有害脱靶效应。结论 来自众多不同类型的临床和遗传学研究的一致证据明确证实 LDL 导致 ASCVD。