Exploring the Causal Roles of Circulating Remnant Lipid Profile on Cardiovascular and Cerebrovascular Diseases: Mendelian Randomization Study

Abstract

Background: Causal evidence of circulating lipids especially the remnant cholesterol with cardiovascular and cerebrovascular disease (CVD) is lacking. This research aimed to explore the causal roles of extensive lipid traits especially the remnant lipids in CVD.

Methods: Two-sample Mendelian randomization (TSMR) analysis was performed based on large-scale meta-analysis datasets in European ancestry. The causal effect of 15 circulating lipid profiles including 6 conventional lipids and 9 remnant lipids on coronary heart disease (CHD) and ischemic stroke (IS), as well as the subtypes, was assessed.

Results: Apolipoprotein B (Apo B), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were still important risk factors for CHD and myocardial infarction (MI) but not for IS. Apo B is the strongest which increased the CHD and MI risk by 44% and 41%, respectively. The odds ratios (ORs) of total TG on CHD and MI were 1.25 (95% confidence interval [CI], 1.13-1.38) and 1.24 (95% CI, 1.11-1.38), respectively. A one standard deviation difference increased TG in medium very-low-density lipoproteins (M.VLDL.TG), TG in small VLDL (S.VLDL.TG), TG in very small VLDL (XS.VLDL.TG), TG in intermediate-density lipoproteins (IDL.TG), TG in very large HDL (XL.HDL.TG), and TG in small HDL (S.HDL.TG) particles also robustly increased the risk of CHD and MI by 9-28% and 9-27%, respectively. TG in very/extremely large VLDL (XXL.VLDL.TG and XL.VLDL.TG) were insignificant or even negatively associated with CHD (in multivariable TSMR), and negatively associated with IS as well.

Conclusion: The remnant lipids presented heterogeneity and two-sided effects for the risk of CHD and IS that may partially rely on the particle size. The findings suggested that the remnant lipids were required to be intervened according to specific components. This research confirms the importance of remnant lipids and provides causal evidence for potential targets for intervention.

Keywords: Mendelian randomization; coronary heart disease; ischemic stroke; remnant lipids.

Figure 1.. Genetic correlation between 15 lipid traits and 5 CVDs. ^*: significant results after Bonferroni correction with P < 0.05/(5 × 15). The color represents the genetic correlation coefficient (r_g), ranging from −1 (blue) to 1 (red). The area of the square represents the size of r_g. In the genetic correlation analysis, small vessel disease was not included due to the small sample size and low heritability that could not perform effective analysis. The correlation coefficients greater than 1 in these results are limited to 1 in this heat map.

Figure 2.. Causal relationship between main lipoprotein/lipids and CVDs. Red error bar: significantly positive association. Green error bar: significantly negative association. Blue error bar: insignificant association. ^*P < 0.05; ^†Significant result after Bonferroni correction; ^§Results with potential horizontal pleiotropic tested using MR-Egger method.

Figure 3.. Causal relationship between circulating remnant lipids and CHD and MI. Red error bar: significantly positive association. Green error bar: significantly negative association. Blue error bar: insignificant association. ^*P < 0.05; ^†Significant result after Bonferroni correction; ^§Results with potential horizontal pleiotropic tested using MR-Egger method.

Figure 4.. In-depth analysis of XXL.VLDL, XL.VLDL, and L.VLDL.TG on CHD and MI adjusting the SNP effects on the candidate traits using the MR-TRYX method. The x-axis represents the weights of each SNP contributes to the causal estimators, and the y-axis represents the product of the causal effect and weights. The slopes represent causal estimators in different models (different lines). Text annotations indicate the identified outlier SNPs and related pleiotropic traits.

Figure 5.. Causal relationship between circulating remnant lipids and IS and subtypes. Red error bar: significantly positive association. Green error bar: significantly negative association. Blue error bar: insignificant association. ^*P < 0.05; ^†Significant result after Bonferroni correction; ^§Results with potential horizontal pleiotropic tested using the MR-Egger method.