脂蛋白(a)的致动脉粥样硬化作用明显强于 LDL：基于载脂蛋白 B 的遗传分析。

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

机构信息

Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.

Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; School of Public Health and Community Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

出版信息

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

DOI:10.1016/j.jacc.2023.10.039

PMID:38233012

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7616706/

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.

摘要

背景

脂蛋白(a)（Lp(a)）被认为是冠心病（CHD）的致病因素，但就每个颗粒而言，其致动脉粥样硬化作用相对于低密度脂蛋白（LDL）尚不明确。

目的

作者基于 Lp(a)和 LDL 每个颗粒均含有 1 个载脂蛋白 B（apoB）这一事实，通过遗传分析解决了这一问题。

方法

利用英国生物库人群进行全基因组关联研究，确定了 2 个单核苷酸多态性簇：一个包含 107 个与 Lp(a)质量浓度相关的变体，另一个包含 143 个与 LDL 浓度相关的变体。在这些 Lp(a)和 LDL 簇中，评估了遗传预测的 apoB 变化与 CHD 风险的关系。

结果

与 LDL-apoB 相同的 50 nmol/L 增加相比，Mendelian 随机化衍生的 Lp(a)-apoB 每增加 50 nmol/L 导致 CHD 的比值比（OR）为 1.28（95%置信区间：1.24-1.33），而 LDL-apoB 为 1.04（95%置信区间：1.03-1.05）。同样，使用多基因评分根据 Lp(a)-apoB 与 LDL-apoB 的差异对受试者进行排名，发现 Lp(a)簇中 CHD 的每 50 nmol/L apoB 的 HR 更高（1.47；95%置信区间：1.36-1.58），而 LDL 簇中为 1.04（95%置信区间：1.02-1.05）。从这些数据中，我们估计 Lp(a)的致动脉粥样硬化作用大约是 LDL 的 6 倍（点估计值为 6.6；95%置信区间：5.1-8.8）。