Importance The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown.

Objective To assess the relative benefits and harms associated with genetic CETP deficiency.

Design, Setting, and Participants This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018.

Exposures Weighted CETP allele scores.

Main Outcomes and Measures Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non–high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency.

Results Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol.

Conclusions and Relevance This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.

重要性 与遗传性胆固醇酯转移蛋白 (CETP) 缺乏症相关的潜在长期临床益处和危害之间的平衡，模拟药物 CETP 抑制，是未知的。

目的 评估与遗传性 CETP 缺陷相关的相对益处和危害。

设计、设置和参与者 本研究调查了 2 个类似的丹麦普通人群的前瞻性队列，从 1991 年 10 月 10 日到 2018 年 12 月 7 日收集了总共 102607 名参与者的数据。

曝光 加权CETP等位基因分数。

主要结局和测量指标 心血管死亡率、缺血性心脏病、心肌梗死、缺血性卒中、外周动脉疾病、血管性痴呆、阿尔茨海默病、全因死亡率和年龄相关性黄斑变性 (AMD)。该研究首先测试了CETP等位基因评分与发病率和死亡率相关，当按比例缩放到非高密度脂蛋白 (HDL) 胆固醇的遗传较低水平（即 17 mg/dL）时，对应于随机评估中观察到的 anacetrapib 与安慰剂的减少Anacetrapib 通过脂质修饰 (REVEAL) 试验的影响。其次，该研究评估了发病率和死亡率的变化在多大程度上与遗传性较低的非高密度脂蛋白胆固醇水平相关。最后，量化了与遗传 CETP 缺陷相关的潜在长期临床益处和危害之间的平衡。对于 AMD，分析还包括与遗传性 CETP 缺陷相关的较高水平的 HDL 胆固醇。

结果 在研究中的 102607 人中，56559 人 (55%) 是女性（中位年龄，58 岁 [IQR，47-67 岁]）。多变量调整后的风险比表明，遗传上较低水平的非 HDL 胆固醇（即 17 mg/dL）与较低的心血管死亡风险相关（风险比 [HR]，0.77 [95% CI，0.62-0.95]） 、缺血性心脏病（HR，0.80 [95% CI，0.68-0.95]）、心肌梗塞（HR，0.72 [95% CI，0.55-0.93]）、外周动脉疾病（HR，0.80 [95% CI，0.63- 1.02]）和血管性痴呆（HR，0.38 [95% CI，0.18-0.80]）和 AMD 风险增加（HR，2.33 [95% CI，1.63-3.30]），但与全因死亡率无关（HR，0.91 [95% CI，0.81-1.02]）、缺血性中风（HR，1.05 [95% CI，0.81-1.36]）或阿尔茨海默病（HR，1.25 [95% CI，0.89-1.76]）。当缩放到更高水平的 HDL 胆固醇时，AMD的风险增加甚至更大。心血管终点风险较低的相当一部分与非高密度脂蛋白胆固醇的遗传水平较低有关，而 AMD 的较高风险与高密度脂蛋白胆固醇的遗传水平较高有关。每 100 万人年，预计 1916 年与遗传性高水平 HDL 胆固醇相关的更多 AMD 事件与 1962 年与遗传性低水平非高密度脂蛋白胆固醇相关的心血管死亡和心肌梗塞事件减少相似。

结论和相关性 本研究表明，遗传性 CETP 缺乏与药物 CETP 抑制作用相似，与较低的心血管发病率和死亡率风险相关，但与 AMD 风险显着升高相关。