Department of Dermatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-Yuan 33305, Taiwan.
Cardiovascular Division, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Tao-Yuan 33305, Taiwan.
Int J Mol Sci. 2023 Sep 28;24(19):14668. doi: 10.3390/ijms241914668.
Previous investigations have suggested an association between the common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.
先前的研究表明，常见的 E670G 多态性与脂蛋白(a)（Lp(a)）水平之间存在关联，以及血浆 PCSK9 水平与 Lp(a)浓度之间存在关联。然而，血浆 PCSK9 与 Lp(a)水平之间的因果关系仍不确定。在这项研究中，我们在 614 名健康的台湾个体中探讨了 E670G 多态性与 Lp(a)水平之间的关联。我们使用来自全基因组关联研究（GWAS）和英国生物库的公开可访问的 PCSK9 和 Lp(a)汇总统计数据，采用两样本 Mendelian 随机化（MR）分析，旨在确定血浆 PCSK9 水平与 Lp(a)浓度之间是否存在因果关系。我们的研究结果表明，E670G G 等位基因与升高的 Lp(a)水平的发生几率降低独立相关。即使在调整了常见的心血管风险因素后，并且无论脂质谱的变化如何，这种关联仍然存在。利用六个与 GWAS 相关的变异作为工具变量来预测血浆 PCSK9 水平的 MR 分析提供了有力的证据，表明血浆 PCSK9 水平与 Lp(a)浓度之间存在因果关系。总之，我们的研究不仅复制了 E670G 多态性与 Lp(a)水平之间的关联，而且通过 MR 分析证实了 PCSK9 水平与 Lp(a)浓度之间的因果关系。
