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Ference BA, Kastelein JJP, Ray KK, et al. Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019;321(4):364–373. doi:10.1001/jama.2018.20045
What is the clinical benefit of lowering plasma triglyceride levels compared with lowering low-density lipoprotein cholesterol levels?
In mendelian randomization analyses involving 654 783 participants, triglyceride-lowering variants in the lipoprotein lipase gene and low-density lipoprotein cholesterol (LDL-C)–lowering variants in the LDL receptor gene were associated with similar lower risk of coronary heart disease per 10-mg/dL lower level of apolipoprotein B (ApoB)–containing lipoproteins (odds ratios of 0.771 and 0.773, respectively).
The clinical benefit of lower triglyceride levels was similar to the clinical benefit of lower LDL-C levels per unit difference in ApoB and may be related to the absolute reduction in ApoB-containing lipoprotein particles.
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.
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.
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).
Conclusions and Relevance
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.
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