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Cited by 183Lipoproteins and Cardiovascular HealthLipid metabolism and disordersGenetic Associations and Epidemiology

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

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Björnson, Elias, Adiels, Martin, Taskinen, Marja-Riitta, Burgess, Stephen, Rawshani, Aidin, Borén, Jan, Packard, Chris J·2023·European Heart Journal
DOI 10.1093/eurheartj/ehad337PMC PMC10576615
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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.

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Graphical Abstract
Graphical Abstract CC BY · PubMed Central
Figure 1 Impact of relative abundance of TG or TRL/remnant-C versus LDL-C on risk of ASCVD event. In statistical models controlling for plasma apoB the influence of variation in the ratio of TG or TRL/remnant-C to LDL-C on the hazard ratio for an incident ASCVD event (MI + coronary revascularisation) was determined. Models were adjusted to apoB=1.066 g/L, sex=female, BMI=26.32 kg/m2, age =56 years, systolic BP=137 mmHg, HbA1C=34.8 mmol/mol. In panels A and B, HDL-C was not included in the model while in panels C and D, the models were further adjusted to HDL-C =1.435 mmol/L. P-values of the respective term (TG per LDL-C and TRL/remnant-C per LDL-C) in the Cox proportional hazards models are indicated in each panel.
Figure 1 Impact of relative abundance of TG or TRL/remnant-C versus LDL-C on risk of ASCVD event. In statistical models controlling for plasma apoB the influence of variation in the ratio of TG or TRL/remnant-C to LDL-C on the hazard ratio for an incident ASCVD event (MI + coronary revascularisation) was determined. Models were adjusted to apoB=1.066 g/L, sex=female, BMI=26.32 kg/m2, age =56 years, systolic BP=137 mmHg, HbA1C=34.8 mmol/mol. In panels A and B, HDL-C was not included in the model while in panels C and D, the models were further adjusted to HDL-C =1.435 mmol/L. P-values of the respective term (TG per LDL-C and TRL/remnant-C per LDL-C) in the Cox proportional hazards models are indicated in each panel.CC BY · PubMed Central
Figure 2 Identification of genes influencing TRL/remnant cholesterol. SNPs were selected from a previously published SNP set (Panel A) or identified from a new GWAS (Panel B). Tier 3 SNPs shown in Panel B were associated with TRL/remnant-C and/or LDL-C at a significance threshold of <5x10-8. Effects are expressed as minor allele/major allele. Annotations ‘1’ and ‘2’ in Panel B denote putative SNP clusters defined by the gradient of effect size on apoB relative to effect size on TRL/remnant-C. Units for apoB are g/L and for TRL/remnant-C mmol/L. For example, SNPs rs11591147 in PCSK9 (denoted ‘A’) and rs1367117 in APOB (‘B’) had effect size ratios of 1.49 and 1.50 while SNPs rs328 in LPL (‘C’) and rs3135506 in APOA5 (‘D’) had ratios of 0.29 and 0.41 respectively. Panels C and D give the frequency distributions for values of the ratio of apoB effect size to TRL/remnant-C effect size (beta coefficients ratio) for each SNP in the Tier 1 and Tier 3 sets respectively. The arrows denote the values used to divide the SNPs in to cluster 1 (0.9 to 3.0) and cluster 2 (-0.75 to +0.75). Numbers of SNPs allocated to each cluster are shown. The number of unallocated SNPs (not falling into the denoted intervals) was 40 for Tier 1 and 163 for Tier 3.
Figure 2 Identification of genes influencing TRL/remnant cholesterol. SNPs were selected from a previously published SNP set (Panel A) or identified from a new GWAS (Panel B). Tier 3 SNPs shown in Panel B were associated with TRL/remnant-C and/or LDL-C at a significance threshold of <5x10-8. Effects are expressed as minor allele/major allele. Annotations ‘1’ and ‘2’ in Panel B denote putative SNP clusters defined by the gradient of effect size on apoB relative to effect size on TRL/remnant-C. Units for apoB are g/L and for TRL/remnant-C mmol/L. For example, SNPs rs11591147 in PCSK9 (denoted ‘A’) and rs1367117 in APOB (‘B’) had effect size ratios of 1.49 and 1.50 while SNPs rs328 in LPL (‘C’) and rs3135506 in APOA5 (‘D’) had ratios of 0.29 and 0.41 respectively. Panels C and D give the frequency distributions for values of the ratio of apoB effect size to TRL/remnant-C effect size (beta coefficients ratio) for each SNP in the Tier 1 and Tier 3 sets respectively. The arrows denote the values used to divide the SNPs in to cluster 1 (0.9 to 3.0) and cluster 2 (-0.75 to +0.75). Numbers of SNPs allocated to each cluster are shown. The number of unallocated SNPs (not falling into the denoted intervals) was 40 for Tier 1 and 163 for Tier 3.CC BY · PubMed Central
Figure 3 Influence of SNP clusters on plasma TG, TRL/remnant-C, VLDL-C and LDL-C relative to change in apoB. SNPs in the Tier 3 set were allocated to clusters according to the ratio of the effect on apoB relative to the effect on TRL/remnant-C. SNPs assigned to cluster 1 (n=553) are denoted by red circles; those assigned to cluster 2 (n=506) are denoted by blue circles. Unassigned SNPs (n=163) are indicated in grey. Effects are expressed as minor allele/major allele. Units for apoB are g/L and for TG, TRL/remnant-C, VLDL-C and LDL-C are mmol/L. SNPs in each cluster with the largest effect size for TRL/remnant-C, and their effect size ratios (apoB relative to TRL/remnant-C) are given in Supplementary Table 5.
Figure 3 Influence of SNP clusters on plasma TG, TRL/remnant-C, VLDL-C and LDL-C relative to change in apoB. SNPs in the Tier 3 set were allocated to clusters according to the ratio of the effect on apoB relative to the effect on TRL/remnant-C. SNPs assigned to cluster 1 (n=553) are denoted by red circles; those assigned to cluster 2 (n=506) are denoted by blue circles. Unassigned SNPs (n=163) are indicated in grey. Effects are expressed as minor allele/major allele. Units for apoB are g/L and for TG, TRL/remnant-C, VLDL-C and LDL-C are mmol/L. SNPs in each cluster with the largest effect size for TRL/remnant-C, and their effect size ratios (apoB relative to TRL/remnant-C) are given in Supplementary Table 5.CC BY · PubMed Central
Figure 4 Association of apoB with TRL-C and ASCVD risk in clusters 1 and 2. Panel A shows for Tier 1 SNPs the association of TRL-C with apoB in each cluster with the exposure allele defined as the variant raising apoB. As for the Tier 3 set in Figure 3, the 380 Tier 1 SNPs were assigned to clusters on the basis of the ratio of effects on apoB relative to TRL/remnant-C; 205 SNPs were allocated to cluster 1, and 135 to cluster 2. Panels B and C show for cluster 1 and 2 respectively each SNPs’ effect on apoB and on ASCVD (prevalent + incident) outcome (note that the x-axis for cluster 1 in Panel B has been truncated to allow better visual comparison with the apoB range for cluster 2 in Panel C). Mendelian randomisation modelling (inverse-variance weighted method) was used to determine for each cluster the odds ratio per population SD change in apoB (0.23 g/L). The ASCVD outcome effect estimates per SD apoB differed for cluster 1 and cluster 2 with non-overlapping 95%CIs as shown. Results were similar for Mendelian randomisation analysis using the contamination mixture method which accommodates potential pleiotropic effects; odds ratio per SD apoB were for cluster 1 SNPs 1.32 [95%CI 1.26-1.42] and for cluster 2 SNPs 1.65 [1.47-1.90] (Supplementary Table 3). The genetic effect on apoB has units of g/L and on TRL/remnant-C (Panel A) has units of mmol/L.
Figure 4 Association of apoB with TRL-C and ASCVD risk in clusters 1 and 2. Panel A shows for Tier 1 SNPs the association of TRL-C with apoB in each cluster with the exposure allele defined as the variant raising apoB. As for the Tier 3 set in Figure 3, the 380 Tier 1 SNPs were assigned to clusters on the basis of the ratio of effects on apoB relative to TRL/remnant-C; 205 SNPs were allocated to cluster 1, and 135 to cluster 2. Panels B and C show for cluster 1 and 2 respectively each SNPs’ effect on apoB and on ASCVD (prevalent + incident) outcome (note that the x-axis for cluster 1 in Panel B has been truncated to allow better visual comparison with the apoB range for cluster 2 in Panel C). Mendelian randomisation modelling (inverse-variance weighted method) was used to determine for each cluster the odds ratio per population SD change in apoB (0.23 g/L). The ASCVD outcome effect estimates per SD apoB differed for cluster 1 and cluster 2 with non-overlapping 95%CIs as shown. Results were similar for Mendelian randomisation analysis using the contamination mixture method which accommodates potential pleiotropic effects; odds ratio per SD apoB were for cluster 1 SNPs 1.32 [95%CI 1.26-1.42] and for cluster 2 SNPs 1.65 [1.47-1.90] (Supplementary Table 3). The genetic effect on apoB has units of g/L and on TRL/remnant-C (Panel A) has units of mmol/L.CC BY · PubMed Central
Figure 5 Association of polygenic scores for cluster 1 and 2 with LDL-C, TRL/remnant-C, TG and ASCVD risk. Polygenic scores (PGS) were constructed for each subject summating the apoB raising alleles (multiplied by their beta coefficient) present in cluster 1 and cluster 2 taken from the GWAS Tier 3 SNP set. The cohort was divided into deciles of PGS and mean measured apoB, LDL-C, TRL-C and TG levels at baseline were determined (Panels A to C). The hazard ratio for ASCVD events (incident MI + coronary revascularisation over the 12 year follow up) was estimated for each decile of PGS in each cluster by Cox proportional-hazards modelling. The black dot in panel D denotes the common reference point of 1.02 g/L apoB. For each cluster, hazard ratios were determined also per 10mg/dL increase in apoB as shown in Panel D.
Figure 5 Association of polygenic scores for cluster 1 and 2 with LDL-C, TRL/remnant-C, TG and ASCVD risk. Polygenic scores (PGS) were constructed for each subject summating the apoB raising alleles (multiplied by their beta coefficient) present in cluster 1 and cluster 2 taken from the GWAS Tier 3 SNP set. The cohort was divided into deciles of PGS and mean measured apoB, LDL-C, TRL-C and TG levels at baseline were determined (Panels A to C). The hazard ratio for ASCVD events (incident MI + coronary revascularisation over the 12 year follow up) was estimated for each decile of PGS in each cluster by Cox proportional-hazards modelling. The black dot in panel D denotes the common reference point of 1.02 g/L apoB. For each cluster, hazard ratios were determined also per 10mg/dL increase in apoB as shown in Panel D.CC BY · PubMed Central
Figure 6 Impact of variation in genes influencing lipolysis and lipoprotein receptors on TRL/remnant and LDL metabolism. In this schematic the putative differential effects of variants of reduced functionality are depicted in boxes. Remnants are defined as lipoprotein particles that have undergone partial lipolysis and remodelling with removal of some core TG and the acquisition of cholesteryl ester by cholesteryl ester transfer protein – mediated exchange.2, 20, 29 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. Further, when lipolysis is slowed there is increased opportunity for cholesteryl ester (CE) to transfer from HDL to TRL, thereby increasing the cholesterol content of remnant particles and lowering HDL-C. 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. 2, 20 Cluster 1 SNPs which reduce the activity of 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.
Figure 6 Impact of variation in genes influencing lipolysis and lipoprotein receptors on TRL/remnant and LDL metabolism. In this schematic the putative differential effects of variants of reduced functionality are depicted in boxes. Remnants are defined as lipoprotein particles that have undergone partial lipolysis and remodelling with removal of some core TG and the acquisition of cholesteryl ester by cholesteryl ester transfer protein – mediated exchange.2, 20, 29 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. Further, when lipolysis is slowed there is increased opportunity for cholesteryl ester (CE) to transfer from HDL to TRL, thereby increasing the cholesterol content of remnant particles and lowering HDL-C. 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. 2, 20 Cluster 1 SNPs which reduce the activity of 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.CC BY · PubMed Central

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Metadata

Authors
Björnson, E., Adiels, M., Taskinen, M.-R., Burgess, S., Rawshani, A., Borén, J., & Packard, C. J.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • University of Helsinki (FI)
  • University of Cambridge (GB)
  • University of Glasgow (GB)
Corresponding author
Borén, Jan
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2023-06-26
Volume
44
Issue
39
Pages
4186-4195
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/ehad337
PMC
PMC10576615
OpenAlex
W4382011883
Cited by
183
References
28
Citations by year
2026: 47 · 2025: 76 · 2024: 50 · 2023: 9
FWCI
48.59
Type
journal article
Language
en
Open access
Licence
Locations
  • European Heart Journal (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by-nc)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • Swedish Research Council
  • Swedish Heart–Lung Foundation (ALFGBG-965404)
  • Sigrid Juselius Foundation
  • Finnish Foundation for Cardiovascular Research
  • Wellcome Trust and the Royal Society (204623/Z/16/Z)
  • United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7)
  • National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014)
  • National Institute for Health Research
  • Department of Health and Social Care
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
remnant cholesterol, LDL cholesterol, coronary heart disease risk, apolipoprotein B, atherogenicity, lipoprotein particle size, lipolysis, single nucleotide polymorphisms, polygenic risk score, Mendelian randomization
MeSH terms
Apolipoproteins B, Cholesterol, Coronary Disease, United Kingdom, Humans, Lipoproteins, Cholesterol, LDL, Triglycerides, Biological Specimen Banks

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