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Lipoprotein(a) Is Markedly More Atherogenic Than LDL
Quick Takes
- Lp(a) is an LDL-like particle containing apolipoprotein (a) linked to one apoB molecule. It is recognized as a causal risk factor for atherosclerotic CVD including risk of CHD/MI, stroke, and aortic valve stenosis. But the strength of the association is not clear as compared to LDL particles.
- The association of genetically predicted variation in Lp(a)-apoB with risk of CHD was compared to that of LDL-apoB using Mendelian randomization-derived odds ratio. Lp(a) was about 6 times more atherogenic than LDL per unit change in apoB per particle.
- However, on a population basis, Lp(a) levels are generally low and even with a higher per-particle atherogenicity, Lp(a) particles will make a much smaller contribution to overall risk compared to the more abundant LDL particles. However, in a sizeable minority of individuals with elevated Lp(a), the contribution of Lp(a) to CHD risk is considerably more significant.
Study Questions:
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. Is the atherogenicity of Lp(a) greater than LDL based on the contribution of each to the number of apolipoprotein B (apoB) particles considering that both contain one apoB molecule per particle?
Methods:
Genome-wide association studies using the UK Biobank population identified two clusters of single nucleotide polymorphisms (SNPs): 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. For studies of the association of CHD with genetically predicted lipoprotein levels, outcomes were the combination of prevalent and incident events (myocardial infarction [MI] and coronary revascularization). For the polygenic score studies, outcomes were incident events occurring during the approximately 12-year follow-up period.
Results:
The Mendelian randomization-derived odds ratio for CHD for a 50 nmol/L higher Lp(a)-apoB was 1.28 (95% confidence interval [CI], 1.24-1.33) compared to 1.04 (95% CI, l.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 versus difference in LDL-apoB revealed a greater hazard ratio for CHD per 50 nmol/L apoB for the Lp(a) cluster (1.47 [95% CI, 1.36-1.58]) compared to the LDL cluster (1.04 [95% CI, 1.02-1.05]). From these data, the estimate of atherogenicity of Lp(a) is approximately six-fold (point estimate of 6.6; 95% CI, 5.1-8.8) greater than that of LDL on a per particle basis.
Conclusions:
The authors 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.
Perspective:
Clinical measurement of Lp(a) is most often in mg/dL. Studies suggest Lp(a) mass concentration would need to be lowered by 50-100 mg/dL to achieve the same risk reduction as a 1.0 mmol/L lowering of LDL cholesterol, but these estimates are not based on the more accurate nmol/L, which does not have a reliable conversion to mg/dL. When necessitated by available data in this study, the conversion factor was derived from a reference that 1 mg/dL = 2.2 nmol/L.
The authors hypothesized that the relationship of Lp(a)-apoB and LDL-apoB to risk of CHD would permit a comparison of the relative atherogenicity of these two lipoprotein species, and that this approach would provide insight into the expected CHD risk reduction from a given lowering of Lp(a). The genetic estimate was derived from the influence of all the known SNPs for Lp(a) and LDL on total apoB.
The accuracy of the method could be validated by using the randomized clinical trials of PCSK9 antibody therapy post-MI and other subsets in which the reduction in cardiovascular event rates was markedly enhanced in those with an elevated Lp(a).
Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Prevention
Keywords: Cholesterol, LDL, Lipoprotein(a)
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