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Triglyceride-Rich Lipoprotein Remnants, LDLs, and Risk of CHD
Quick Takes
- Triglyceride-rich lipoprotein (TRL)/remnant-C (VLDL remnant-C) is a strong predictor of CHD risk independent of apoB and LDL-C.
- The increment in CHD risk per apoB particle is two-fold greater in the single-nucleotide polymorphism cluster with the larger effect on TRL/remnants than that associated with hepatic clearance.
- TRL/remnant particles have a substantially greater atherogenicity than LDL, inferring that targeting post-prandial lipids with diet and novel drugs have promise for reducing CV events.
Study Questions:
What is the strength of the relationship of triglyceride-rich lipoproteins (TRLs) with risk of coronary heart disease (CHD) compared with low-density lipoprotein cholesterol (LDL-C)?
Methods:
The authors used the UK Biobank evaluating the entire genome of 805,326 single-nucleotide polymorphisms (SNPs) in over 500,000 men and women (mean age 56.5 years) with available lipids including directly measured LDL-C, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and derived TRL/remnant-C as non–HDL-C minus LDL-C. None were treated with statins. Follow-up was 12 years for incident and prevalent CHD events including myocardial infarction and coronary revascularization. Odds ratios for CHD outcomes were determined per unit change (1.0 mmol/L for lipids or 1.0 g/L for apolipoprotein B [apoB]). Genome-wide association studies (GWAS) were performed to identify SNPs associated with TRL/remnant-C and/or LDL-C. The final set was 1,125 SNPs. Lipoprotein(a) was excluded. The SNPs identified were assigned to clusters based on their effects on TRL/remnant-C (representing the concentration of TRL/remnant particles) relative to total apoB (representing the concentration of all apoB-containing lipoproteins).
Polygenic risk scores were created by SNPs within clusters. Cluster 1 included SNPs that affected the receptor pathways (hepatic clearance) for LDL and TRL remnants with the former dominant, and cluster 2 SNPs affecting lipolysis as rate of formation of circulating TRL remnants.
Results:
Data were available for 48,000 subjects in whom there were 29,000 events. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apoB. Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 (95% confidence interval [CI], 1.99–3.36) and 1.37 (95% CI, 1.27–1.48), respectively.
The CHD odds ratio per standard deviation (SD) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI, 1.58–1.96), which was significantly greater than the CHD odds ratio per SD higher apoB in cluster 1 (1.33; 95% CI, 1.26–1.40). A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk.
Conclusions:
Distinct SNP clusters appear to impact differentially on remnant particles and LDL. The findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.
Perspective:
There has been much written regarding the incremental value of post-prandial lipids for assessing risk of atherosclerotic cardiovascular disease rather than fasting to calculate LDL-C, the target of statins. But statin benefit is limited to reducing LDL-C and total apoB, which lowers CV event rates by about 30%, leaving a large residual risk for which there are many nonlipid and other lipid risk factors. About 75% of time is spent post-prandial when lipid atherogenicity may be highest. This lends support for the popular plant-based diet with avoidance of high glycemic index foods that increase very-low-density lipoprotein (VLDL) remnant particles. The present study supports the concept not because triglyceride levels are a risk factor, but rather, they are associated with cholesterol-rich VLDL remnant particles, which as has been presented, are more highly atherogenic than LDL and apoB.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Lipid Metabolism
Keywords: Apolipoproteins B, Dyslipidemias, Triglycerides
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