Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study

Abstract

Aims: The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved.

Methods and results: Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (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. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. 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.

Conclusion: Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.

Keywords: Apolipoprotein B; Cardiovascular disease; Genetics; LDL cholesterol; Mendelian randomization; Remnants; Single-nucleotide polymorphisms; Triglyceride; UK Biobank.

Structured Graphical Abstract

Cluster-based SNP analysis showing higher per particle atherogenicity for triglyceride-rich lipoproteins/remnants than for low density lipoproteins.

Figure 1

Identification of genes influencing TRL/remnant cholesterol. Plotting the beta coefficients (beta coefficients can be interpreted as the amount that a SNP, per effect-allele, increases or decreases the biomarker in question. Hence, it can be interpreted as a genetically predicted change in apoB, LDL-C, and TRL/remnant-C. For LDL-C and TRL/remnant-C, the effect, per allele, is measured in mmol/L cholesterol, and for apoB, the effect is measured in g/L) for TRL/remnant-C vs. apoB or LDL-C (for the 1125 SNPs identified in the GWAS) revealed the presence of two clusters. In one cluster, SNPs (marked blue) were characterized by having a larger effect size on TRL/remnant-C relative to apoB (A) or to LDL-C (B), while in the other cluster (marked red), SNPs had a smaller effect on TRL/remnant-C relative to apoB or to LDL-C. (C) Histogram of the TRL/remnant-C to apoB beta coefficient ratio for the 1125 SNPs. The two clusters were defined formally based on range limits for the ratio of TRL/remnant-C to apoB. Single-nucleotide polymorphisms were allocated to cluster 1 if they had a ratio between 0.33 and 1.1 and to cluster 2 if the ratio was >1.33. (D) Distribution of SNP effect sizes on TRL/remnant-C relative to LDL-C in the two defined clusters.

Figure 2

Association of apoB with TRL-C and CHD risk in clusters 1 and 2. (A) Association of TRL/remnant-C with apoB in each SNP cluster with the exposure allele defined as the variant raising apoB. ApoB has units of g/L, and TRL/remnant-C has units of mmol/L. Panels (B) and (C) show, for clusters 1 and 2, respectively, each SNPs’ effect on apoB and on CHD (prevalent + incident) outcome [note that the x-axis for cluster 1 in (B) has been truncated to allow better visual comparison with the apoB range for cluster 2 in (C)]. Data points in (B) and (C) are colored as less translucent the lower the P value for apoB. Mendelian randomization modeling (inverse variance–weighted method) was used to determine the odds ratio (OR) for CHD risk per Sd change in apoB (0.23 g/L) for each cluster in the cohort of subjects off or on lipid-lowering treatment.

Figure 3

Association of polygenic scores for clusters 1 and 2 with TRL/remnant-C and CHD risk. Subjects without a history of CHD were divided into deciles according to the cluster-specific PGS; for each PGS, the relationship of apoB to TRL/remnant-C was examined (A). For illustrative purposes, hazard ratios (HRs) for CHD events (using decile 5 as referent for each PGS) were estimated for each decile of cluster 1 PGS and cluster 2 PGS (B). To compare the gradient of association of apoB with CHD risk between clusters, a single Cox model was constructed that included the scaled cluster 1 PGS and cluster 2 PGS as continuous variables. The derived HRs per 1 Sd change in apoB are given in (B).

Figure 4

Impact of variation in genes influencing lipolysis and those influencing lipoprotein receptors on TRL/remnant and LDL metabolism. In this schematic, the putative differential effects of variants of reduced functionality are depicted in boxes. Triglyceride-rich lipoproteins remnants are defined as lipoprotein particles that have undergone partial lipolysis.^,, SNPs in genes that cause a reduction in the efficiency of lipolysis (‘cluster 2’ SNPs) potentially increase the rate of TRL/remnant particle formation but have smaller effects on LDL. Since TRL/remnants contain apoB, there is a modest increment in plasma total apoB levels. Metabolic studies have established that VLDL- and chylomicron-remnants are cleared from the circulation by the LDL receptor and possibly other receptors binding to apoB on the particle surface and facilitating endocytosis and degradation.^, Cluster 1 SNPs which reduce the activity of the LDL receptor or alter the ligand, apoB, affect remnant clearance and cause increases in the concentration of both TRL/remnant and LDL particles with a consequent substantial rise in plasma apoB.