Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease

Importance

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.

Objective

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 theLPLgene and LDL-C–lowering variants in theLDLRgene, 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.

Exposures

Differences in plasma triglyceride, LDL-C, and ApoB levels associated with theLPLandLDLRgenetic scores.

Main Outcomes and Measures

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.

Results

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, theLPLscore 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 theLDLRscore 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, theLPLandLDLRscores 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 × 10⁻³⁸and 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).

Conclusions and Relevance

Triglyceride-loweringLPLvariants and LDL-C–loweringLDLRvariants 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.