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

Abstract

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 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.

Exposures: 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.

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, 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.

Figure 1.. Associations Between the Lipoprotein Lipase (LPL) and LDL Receptor Gene (LDLR) Genetic Scores With Triglycerides, Low-Density Lipoprotein Cholesterol (LDL-C), and Risk of Coronary Heart Disease (CHD) per 10-mg/dL Lower Concentration of Apolipoprotein B (ApoB)–Containing Lipoproteins

Triglycerides are carried in plasma by ApoB-containing triglyceride-rich lipoproteins while cholesterol is carried predominantly by ApoB-containing low-density lipoproteins. Changes in plasma triglycerides and LDL-C concentration are thus markers of the corresponding changes in the concentration of the ApoB-containing lipoproteins that transport these lipids. Variants in the LPL gene that increase LPL activity are associated with lower triglycerides and a corresponding lower ApoB concentration, while variants in the LDLR gene that increase activity of the LDL receptor are associated with lower LDL-C and a corresponding lower ApoB. The figure shows that for each 10-mg/dL lower plasma ApoB concentration associated with variants in the LPL score, there is a corresponding 69.9-mg/dL lower triglyceride level, no change in LDL-C, and a lower risk of CHD (odds ratio, 0.771 [95% CI, 0.741-0.802]). By contrast, for the same 10-mg/dL lower plasma ApoB concentration associated with variants in the LDLR score, there is a corresponding 14.1-mg/dL lower LDL-C level, no change in triglycerides, and a similar lower risk of CHD (odds ratio, 0.773 [95% CI, 0.747-0.801]). Therefore, despite being associated with changes in different lipids, the LPL and LDLR scores were associated with similar lower risk of CHD for the same lower plasma ApoB concentration. The data presented are for the associations of the LPL and LDLR genetic scores with risk of CHD per 10-mg/dL decrease in ApoB-containing lipoproteins in all 654 783 participants included in the study. The associations of either score with changes in triglycerides and LDL-C per 10-mg/dL lower level of ApoB-containing lipoproteins are from up to 305 699 participants enrolled in the Global Lipid Genetics Consortium. Boxes represent effect size estimates and lines represent 95% CIs.

Figure 2.. Association of Genetic Variants and Genetics Scores With Triglycerides, Low-Density Lipoprotein Cholesterol (LDL-C), and Risk of Coronary Heart Disease (CHD) per 10-mg/dL Lower Concentration of Apolipoprotein B (ApoB)–Containing Lipoproteins

The figure shows the associations with triglycerides, LDL-C, and risk of CHD for the same 10-mg/dL lower ApoB-containing lipoprotein concentration for variants in the LPL and LDLR scores as compared with variants in the genes that encode the targets of current therapies that lower LDL-C through the LDL receptor pathway; variants in the genes that encode the targets of potential therapies that lower triglycerides through the LPL pathway; and variants in the APOB gene. For example, each 10-mg/dL lower plasma ApoB concentration associated with the partial loss-of-function rs11591147 variant in the PCSK9 gene was associated with a corresponding 18.0-mg/dL lower LDL-C level, no change in triglycerides, and a lower risk of CHD (odds ratio, 0.774 [95% CI, 0.721-0.832]). By contrast, for the same 10-mg/dL lower plasma ApoB concentration associated with the functional rs116843064 variant in the ANGPTL4 gene, there was a corresponding 69.4-mg/dL lower triglyceride level, no change in LDL-C, and a similar lower risk of CHD (odds ratio, 0.726 [95% CI, 0.609-0.865]). Furthermore, for the same 10-mg/dL lower plasma ApoB concentration associated with variants in the APOB gene score, there was a corresponding 9.7-mg/dL lower triglyceride level, 15.6-mg/dL lower LDL-C level, and a similar lower risk of CHD (odds ratio, 0.778 [95% CI, 0.737-0.821]). Despite a range of associated changes in triglycerides, LDL-C, or both, all genetic variants and genetic scores were associated with similar lower risk of CHD for the same 10-mg/dL lower plasma ApoB concentration. The APOB score is composed of the 8 independently inherited variants in the APOB gene listed in the figure. Boxes represent effect size estimates and lines represent 95% CIs. Associations with CHD per 10-mg/dL lower ApoB were measured in all 654 783 participants included in the study; associations with changes in triglycerides and LDL-C per 10-mg/dL lower ApoB were measured in up to 305 699 participants from the Global Lipid Genetics Consortium.

Figure 3.. Log-Linear Association Between Absolute Differences in Apolipoprotein B (ApoB) and Lower Risk of Coronary Heart Disease (CHD)

The associations of each genetic variant with ApoB concentration is plotted against its unadjusted association with CHD, expressed as a proportional lower risk (calculated as [1−OR_CHD]×100). Variants in the genes that encode the targets of therapies that lower triglycerides through the LPL pathway are marked with blue labels, and variants in the genes that encode the targets of therapies that lower LDL-C through upregulation of the LDL receptor are marked by red labels. Circles represent the associated absolute change in ApoB and corresponding proportional lower risk of CHD for each variant. The horizontal lines through each circle represents ±1 standard errors for the associated absolute change in ApoB for each variant; and the vertical line through each circle represents ±1 standard errors for the associated proportional lower risk of CHD. Associations with CHD were measured in all 654 783 participants included in the study; associations with ApoB were measured in a meta-analysis of 14 studies including up to 84 324 participants.