Ference BA, et al. - In Mendelian randomization analyses with 654,783 participants, researchers compared the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and low-density lipoprotein cholesterol (LDL-C)–lowering variants in the LDL receptor gene (LDLR) with cardiovascular disease risk per unit change in apolipoprotein B (ApoB). Findings suggested both triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were linked with a comparable lower risk of CHD per unit difference in ApoB. The clinical advantage of reducing triglyceride and LDL-C levels may, therefore, be proportional to the absolute change in ApoB.

Methods

• This investigation assessing the correlations 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 recruited in 63 cohort or case-control studies carried out in North America or Europe between 1948 and 2017.
• Exposures included differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores.
• Main outcomes and measures included 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, involving 91,129 CHD cases, were included (mean age, 62.7 years; 51.4% women).
• The LPL score was correlated 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 for each 10-mg/dL lower level of ApoB-containing lipoproteins.
• On the other hand, the LDLR score was related to 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 linked to 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 links between triglyceride and LDL-C levels with CHD risk 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).