Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

中文翻译：

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胆固醇酯转移蛋白的脂蛋白特征和 HMG-CoA 还原酶抑制。

胆固醇酯转移蛋白 (CETP) 抑制可降低血管事件风险，但其对低密度脂蛋白 (LDL) 胆固醇的影响令人困惑。在这里，我们阐明了 CETP 遗传抑制与详细脂蛋白测量的关联，并将其与 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 的遗传抑制进行了比较。我们使用与较低 CETP 表达相关的等位基因 (rs247617) 来模拟 CETP 抑制，并使用与较低 HMGCR 表达相关的等位基因 (rs12916) 来模拟他汀类药物的众所周知的效果以进行比较。该研究由 65,427 名欧洲血统的参与者组成，他们通过核磁共振波谱分析了详细的脂蛋白亚类分析。遗传关联被缩放到冠心病 (CHD) 的相对风险降低 10%。在 8 年的随访期间，我们还检查了 3 个基于人群的队列中脂蛋白亚类测量值与 CHD 事件风险的观察关联，共 616 例病例和 13,564 例对照。CETP 和 HMGCR 的遗传抑制导致与通过 Friedewald 方程估计的 LDL 胆固醇浓度几乎相同的关联。HMGCR 的抑制与所有含载脂蛋白 B 的脂蛋白的较低胆固醇浓度具有相对一致的关联。相比之下，CETP 抑制的关联在较低残留和极低密度脂蛋白 (VLDL) 胆固醇上更强，但与由粒径（直径 18-26 nm）定义的 LDL 中的胆固醇浓度没有关联（- 0.02 SD LDL 由粒径定义；95% CI：CETP 为 -0.10 至 0.05 对比 -0.24 SD，HMGCR 的 95% CI -0.30 至 -0.18）。CETP 的抑制与所有高密度脂蛋白 (HDL) 颗粒中甘油三酯的比例较低密切相关。在观察性分析中，HDL 亚类中较高的甘油三酯成分与较高的 CHD 风险相关，与总胆固醇和甘油三酯无关（在非常大的 HDL 中，每 1 SD 较高的甘油三酯成分的最强风险比为 1.35；95% CI：1.18-1.54）。总之，CETP 抑制似乎不会影响大小特异性的 LDL 胆固醇，但可能通过降低其他致动脉粥样硬化、含载脂蛋白 B 的脂蛋白（如残余和 VLDL）的浓度来降低 CHD 风险。抑制 CETP 还会降低 HDL 颗粒中的甘油三酯成分，这一现象反映了循环 HDL、甘油三酯、和含载脂蛋白 B 的颗粒，并且在观察性分析中与较低的 CHD 风险相关。我们的结果表明，传统的复合脂质测定可能会掩盖新兴脂质改变疗法的异质效应。