Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition

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.

胆固醇酯转移蛋白（Cholesteryl ester transfer protein, CETP）抑制剂可降低血管事件风险，但学界对其对低密度脂蛋白（low-density lipoprotein, LDL）胆固醇的影响仍存在诸多困惑。本研究旨在明确CETP基因抑制与脂蛋白详细表型的关联，并将其与3-羟基-3-甲基戊二酰辅酶A还原酶（3-hydroxy-3-methylglutaryl-coenzyme A reductase, HMGCR）的基因抑制效应进行对比。
我们采用与CETP表达降低相关的等位基因（rs247617）模拟CETP抑制效应，同时采用与HMGCR表达降低相关的等位基因（rs12916）模拟他汀类药物的已知效应以作为对照。本研究共纳入65427名欧洲血统参与者，所有参与者均接受了基于核磁共振波谱法（nuclear magnetic resonance spectroscopy）的脂蛋白亚类详细分型。遗传关联分析按冠心病（coronary heart disease, CHD）相对风险降低10%的尺度进行标化。我们还在3个基于人群的队列中分析了脂蛋白亚类表型与新发CHD风险的观察性关联，这些队列在8年随访期间共纳入616例新发CHD病例与13564名对照个体。
CETP与HMGCR的基因抑制效应在弗莱德沃尔德方程（Friedewald equation）估算的LDL胆固醇浓度上呈现近乎一致的关联。HMGCR抑制对所有含载脂蛋白B（apolipoprotein B）脂蛋白的胆固醇浓度降低均表现出相对一致的效应。与之相反，CETP抑制对残余胆固醇与极低密度脂蛋白（very-low-density lipoprotein, VLDL）胆固醇的降低作用更强，但对按颗粒大小划分的LDL胆固醇（直径18~26nm）无显著关联（CETP组：−0.02标准差，95%置信区间：−0.10~0.05；HMGCR组：−0.24标准差，95%置信区间：−0.30~−0.18）。CETP抑制与所有高密度脂蛋白（high-density lipoprotein, HDL）颗粒内甘油三酯比例的降低显著相关。
在观察性分析中，HDL亚类内甘油三酯组成升高与CHD风险升高独立相关，且不受总胆固醇与甘油三酯水平影响（每1标准差升高的超大HDL颗粒甘油三酯组成对应的最强风险比为1.35；95%置信区间：1.18~1.54）。
综上，CETP抑制似乎并不会影响按颗粒大小划分的LDL胆固醇，但可能通过降低其他致动脉粥样硬化的含载脂蛋白B脂蛋白（如残余胆固醇与VLDL）的浓度来降低CHD风险。CETP抑制还可降低HDL颗粒内的甘油三酯组成，这一现象反映了循环HDL、甘油三酯与含载脂蛋白B颗粒的联合效应，且在观察性分析中与更低的CHD风险相关。本研究结果表明，传统的复合脂质检测可能会掩盖新兴脂质调控疗法的异质性效应。