Association of Triglyceride-Lowering <i>LPL</i> Variants and LDL-C–Lowering <i>LDLR</i> Variants With Risk of Coronary Heart Disease
Authors: Brian A. Ference, John J. P. Kastelein, Kausik K. Ray, Henry N. Ginsberg, M. John Chapman, Chris J. Packard, Ulrich Laufs, Clare Oliver-Williams, Angela M. Wood, Adam S. Butterworth, Emanuele Di Angelantonio, John Danesh, Stephen J. Nicholls, Deepak L. Bhatt, Marc S. Sabatine, Alberico L. Catapano
Journal: JAMA (2019)

<h3>Importance</h3> 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. <h3>Objective</h3> To compare the association of triglyceride-lowering variants in the lipoprotein lipase (<i>LPL</i>) gene and LDL-C–lowering variants in the LDL receptor gene (<i>LDLR</i>) with the risk of cardiovascular disease per unit change in ApoB. <h3>Design, Setting, and Participants</h3> Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the<i>LPL</i>gene and LDL-C–lowering variants in the<i>LDLR</i>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. <h3>Exposures</h3> Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the<i>LPL</i>and<i>LDLR</i>genetic scores. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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<i>LPL</i>score was associated with 69.9-mg/dL (95% CI, 68.1-71.6;<i>P</i> = 7.1 × 10<sup>−1363</sup>) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4;<i>P</i> = .04) higher LDL-C levels; while the<i>LDLR</i>score was associated with 14.2-mg/dL (95% CI, 13.6-14.8;<i>P</i> = 1.4 × 10<sup>−465</sup>) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9;<i>P</i> = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the<i>LPL</i>and<i>LDLR</i>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],<i>P</i> = 3.9 × 10<sup>−38</sup>and OR, 0.773 [95% CI, 0.747-0.801],<i>P</i> = 1.1 × 10<sup>−46</sup>, 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],<i>P</i> = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055],<i>P</i> = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798],<i>P</i> = 7.51 × 10<sup>−20</sup>). <h3>Conclusions and Relevance</h3> Triglyceride-lowering<i>LPL</i>variants and LDL-C–lowering<i>LDLR</i>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.