Triglyceride-Rich Lipoprotein Remnants, LDLs, and Risk of CHD
- 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.
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)?
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.
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.
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.
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.
Keywords: Apolipoproteins B, Dyslipidemias, Triglycerides
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