Centre for Naturally Randomized Trials, University of Cambridge, Cambridge, United Kingdom.
Institute for Advanced Studies, University of Bristol, Bristol, United Kingdom.
JAMA. 2019 Jan 29;321(4):364-373. doi: 10.1001/jama.2018.20045.
Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels.
To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB.
DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017.
Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.
Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins.
A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20).
Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
重要性：载脂蛋白 B（ApoB）所含脂蛋白颗粒可携带甘油三酯和胆固醇在血浆中。目前尚不清楚降低血浆甘油三酯水平是否与降低低密度脂蛋白胆固醇（LDL-C）水平同样能降低心血管事件的风险。
目的：比较脂蛋白脂肪酶（LPL）基因中的甘油三酯降低变体和 LDL 受体基因（LDLR）中的 LDL-C 降低变体与载脂蛋白 B（ApoB）每单位变化的心血管疾病风险之间的关联。
设计、设置和参与者：孟德尔随机化分析评估分别由 LPL 基因中的甘油三酯降低变体和 LDLR 基因中的 LDL-C 降低变体组成的遗传评分与北美或欧洲在 1948 年至 2017 年期间进行的 63 项队列或病例对照研究中参与者的心血管事件风险之间的关联。
暴露：与 LPL 和 LDLR 遗传评分相关的血浆甘油三酯、LDL-C 和 ApoB 水平的差异。
主要结果和措施：每降低 10-mg/dL 载脂蛋白 B 脂蛋白的冠心病（CHD）的比值比（OR）-定义为冠心病死亡、心肌梗死或冠状动脉血运重建。
结果：共纳入 654783 名参与者，包括 91129 例 CHD（平均年龄 62.7 岁，51.4%为女性）。对于每降低 10-mg/dL 的载脂蛋白 B 脂蛋白，LPL 评分与 69.9-mg/dL（95%CI，68.1-71.6；P=7.1×10-1363）的甘油三酯水平降低和 0.7-mg/dL（95%CI，0.03-1.4；P=0.04）的 LDL-C 水平升高相关；而 LDLR 评分与 14.2-mg/dL（95%CI，13.6-14.8；P=1.4×10-465）的 LDL-C 降低和 1.9-mg/dL（95%CI，0.1-3.9；P=0.04）的甘油三酯降低相关。尽管这些相关脂质水平存在差异，但 LPL 和 LDLR 评分与每降低 10-mg/dL 的载脂蛋白 B 脂蛋白的 CHD 风险降低的相关性相似（OR，0.771[95%CI，0.741-0.802]，P=3.9×10-38 和 OR，0.773[95%CI，0.747-0.801]，P=1.1×10-46，分别）。在多变量孟德尔随机化分析中，调整 ApoB 差异后，甘油三酯和 LDL-C 水平与 CHD 风险的相关性变为无效（甘油三酯：OR，1.014[95%CI，0.965-1.065]，P=0.19；LDL-C：OR，1.010[95%CI，0.967-1.055]，P=0.19；ApoB：OR，0.761[95%CI，0.723-0.798]，P=7.51×10-20）。
结论和相关性：载脂蛋白 B 降低的甘油三酯 LPL 变体和 LDL-C 降低的 LDLR 变体与每单位 ApoB 差异的 CHD 风险降低具有相似的相关性。因此，降低甘油三酯和 LDL-C 水平的临床益处可能与 ApoB 的绝对变化成正比。
