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. 2024 Jan 23;83(3):385-395.
doi: 10.1016/j.jacc.2023.10.039.

Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis

Elias Björnson  1 , Martin Adiels  2 , Marja-Riitta Taskinen  3 , Stephen Burgess  4 , M John Chapman  5 , Chris J Packard  6 , Jan Borén  7
Affiliations

Lipoprotein(a) Is Markedly More Atherogenic Than LDL: An Apolipoprotein B-Based Genetic Analysis

Elias Björnson et al. J Am Coll Cardiol. .

Abstract

Background: Lipoprotein(a) (Lp(a)) is recognized as a causal factor for coronary heart disease (CHD) but its atherogenicity relative to that of low-density lipoprotein (LDL) on a per-particle basis is indeterminate.

Objectives: The authors addressed this issue in a genetic analysis based on the fact that Lp(a) and LDL both contain 1 apolipoprotein B (apoB) per particle.

Methods: Genome-wide association studies using the UK Biobank population identified 2 clusters of single nucleotide polymorphisms: one comprising 107 variants linked to Lp(a) mass concentration, the other with 143 variants linked to LDL concentration. In these Lp(a) and LDL clusters, the relationship of genetically predicted variation in apoB with CHD risk was assessed.

Results: The Mendelian randomization-derived OR for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% CI: 1.24-1.33) compared with 1.04 (95% CI: 1.03-1.05) for the same increment in LDL-apoB. Likewise, use of polygenic scores to rank subjects according to difference in Lp(a)-apoB vs difference in LDL-apoB revealed a greater HR for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47; 95% CI: 1.36-1.58) compared with the LDL cluster (1.04; 95% CI: 1.02-1.05). From these data, we estimate that the atherogenicity of Lp(a) is approximately 6-fold (point estimate of 6.6; 95% CI: 5.1-8.8) greater than that of LDL on a per-particle basis.

Conclusions: We conclude that the atherogenicity of Lp(a) (CHD risk quotient per unit increase in particle number) is substantially greater than that of LDL. Therefore, Lp(a) represents a key target for drug-based intervention in a significant proportion of the at-risk population.

Keywords: LDL cholesterol; Mendelian randomization; UK Biobank; cardiovascular disease; lipoprotein(a).

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Conflict of interest statement

Funding Support and Author Disclosures The work in this paper was supported by grants from Swedish Research Council, Swedish Heart Lung Foundation, from the Swedish state under the agreement between the Swedish government and the county councils; the ALF-agreement (ALFGBG-965404), Sigrid Juselius Foundation, Helsinki, Finland, and the Finnish Foundation for Cardiovascular Research. Dr Burgess is supported by the Wellcome Trust (225790/Z/22/Z). This research was funded by United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and supported by the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). This research has been conducted using the open-access UK Biobank Resource under application number [53308]. Thus, the study is exempt from ethical review board approval. Dr Taskinen has received honoraria from Novartis, Akcea, Amgen, Novo Nordisk, Mylan, Chiesi Pharma, and Eli Lilly. Dr Borén has received honoraria from Novartis, Novo Nordisk, Akcea, Amgen, and Pfizer. Dr Chapman has received honoraria from Amgen, Amarin, AstraZeneca, Daiichi-Sankyo, Kowa, Lexicon, MSD, Regeneron, Sanofi, and Pfizer. Dr Packard has received honoraria from Amgen, Amarin, MSD, Dalcor, Novartis, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1. Effects of SNP clusters on plasma apoB and on Lp(a) levels.
Panel A: Relationship of effect sizes (beta coefficients*) for plasma apoB and Lp(a) mass concentration for ‘Lp(a)’ cluster (blue) and ‘LDL’ SNP cluster (yellow). SNPs in the Lp(a) cluster affected both Lp(a) and apoB; SNPs in the ‘LDL’ cluster affected apoB but not Lp(a). Panel B Quantitative association of genetically predicted variation in Lp(a) mass concentration with Lp(a)-apoB (both in nmol/l) for ‘Lp(a)’ cluster. The two variables show good agreement, with the regression line near to unity. Thus, the selection criteria were successful in identifying SNP sets with the required properties. * Each data point represents the calculated beta-coefficient (and standard error) for each SNP. A beta coefficient is the mean change in the exposure (plasma levels of Lp(a) or apoB) in a population resulting from that population having one extra effect-allele. For example, a plasma apoB beta-coefficient for SNP X of 50 nmol/l means that heterozygotes for SNP X have, on average, 50 nmol/l higher apoB compared to people without the SNP. Results in the figure show effect of the minor vs major allele; negative values indicate the minor allele has a lowering effect.
Figure 2
Figure 2. Relationship of CHD risk to LDL-apoB and Lp(a)-apoB.
Panel A: Scatter plot of genetic effect sizes (beta-coefficients, with standard errors – see Figure legend 1 for further explanation) of LDL-apoB versus the genetic effect on CHD outcomes. B: Scatter plot of genetic effect sizes of Lp(a)-apoB against the genetic effect on CHD outcomes. The slope of the association in the ‘Lp(a)-cluster’ was greater than that in the ‘LDL’ cluster. The regression lines in A and B are calculated using inverse-variance weighting and thus the slope is interpreted as a log odds ratio (i.e. it is identical to the MR-model log odds ratio estimate).
Figure 3
Figure 3. Relating apoB to CHD risk using ‘Lp(a)’ and ‘LDL’ PGSs.
Two polygenic scores (PGS) based on the variants in each genetic cluster were constructed. Subjects were ranked by ‘LDL’ PGS and then divided into ventiles (Panel A). Separately, subjects were ranked into ventiles of ‘Lp(a)’ PGS (Panel B) (N≈24360 in each ventile). For each ventile in each of the PGS, the mean measured plasma apoB and observed CHD incidence rate were plotted against each other. For each PGS, the CHD hazard ratio per 50 nmol/l apoB was calculated by means of Cox proportional hazards modelling (adjusting for sex, BMI, age and systolic blood pressure).
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References

    1. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43:3925–3946. doi: 10.1093/eurheartj/ehac361. - DOI - PMC - PubMed
    1. Kronenberg F, Mora S, Stroes ESG. Consensus and guidelines on lipoprotein(a) - seeing the forest through the trees. Curr Opin Lipidol. 2022;33:342–352. doi: 10.1097/MOL.0000000000000855. - DOI - PMC - PubMed
    1. Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e48–e60. doi: 10.1161/ATV.0000000000000147. - DOI - PMC - PubMed
    1. Kaiser Y, van der Toorn JE, Singh SS, et al. Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification. Eur Heart J. 2022;43:3960–3967. doi: 10.1093/eurheartj/ehac377. - DOI - PMC - PubMed
    1. Nurmohamed NS, Kraaijenhof JM, Stroes ESG. Lp(a): a New Pathway to Target? Curr Atheroscler Rep. 2022;24:831–838. doi: 10.1007/s11883-022-01060-4. - DOI - PMC - PubMed

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