Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China.
Department of Radiology, Shanghai Eighth People's Hospital, No. 8. Caobao Road, Xuhui District, Shanghai, 200235, China.
Cardiovasc Toxicol. 2024 Dec;24(12):1364-1379. doi: 10.1007/s12012-024-09930-w. Epub 2024 Oct 11.
Previous observational studies have explored the association between serum lipids, apolipoproteins, and adverse ventricular/aortic structure and function. However, whether a causal link exists is uncertain. This study employed a two-sample Mendelian randomization (MR), colocalization, reverse, and multivariable MR (MVMR) approach to examine the causal associations among five serum lipids, two apolipoproteins, and 32 cardiac magnetic resonance (CMR) traits. Utilizing single-nucleotide polymorphisms (SNPs) linked to serum lipids and apolipoproteins as instrumental variables. CMR traits from seven independent genome-wide association studies served as preclinical endophenotypes, offering insights into aortic and cardiac structure/function. The primary analysis utilized a random-effects inverse variance method (IVW), followed by sensitivity and validation analyses. In the primary IVW MR analyses, genetically predicted low-density lipoprotein cholesterol (LDL-C) levels were positively correlated with increased descending aorta strain (DAo strain) (β = 0.098; P = 2.69E-07) and ascending aorta strain (AAo strain) (β = 0.079; P = 5.19E-05). Genetically predicted high-density lipoprotein cholesterol (HDL-C) levels were positively correlated with left ventricular radial peak diastolic strain rate (LV-PDSRll) (β = 0.176; P = 2.89E-05) and the left ventricular longitudinal peak diastolic strain rate (LV-PDSRrr) (β = 0.059; P = 2.44E-06), and negatively correlated with left ventricular regional wall thickness (LVRWT). While apolipoprotein B (ApoB) levels were positively correlated with AAo strain (β = 0.076; P = 1.16E-05), DAo strain (β = 0.065; P = 2.77E-05). A shared causal variant was identified to demonstrate the associations of ApoB with AAo strain and DAo strain using colocalization analysis. Sensitivity analyses confirmed the robustness of these associations. Targeting lipid and apolipoprotein levels through interventions may provide novel strategies for the primary prevention of CVDs.
先前的观察性研究探讨了血清脂质、载脂蛋白与不良室性/主动脉结构和功能之间的关系。然而，目前尚不确定两者之间是否存在因果关系。本研究采用两样本 Mendelian 随机化（MR）、共定位、反向和多变量 MR（MVMR）方法，研究了五种血清脂质、两种载脂蛋白与 32 项心脏磁共振（CMR）特征之间的因果关系。利用与血清脂质和载脂蛋白相关的单核苷酸多态性（SNP）作为工具变量。来自 7 项独立全基因组关联研究的 CMR 特征作为临床前表型，为主动脉和心脏结构/功能提供了深入了解。主要分析采用随机效应逆方差法（IVW），随后进行敏感性和验证分析。在主要的 IVW-MR 分析中，遗传预测的低密度脂蛋白胆固醇（LDL-C）水平与降主动脉应变（DAo 应变）（β=0.098；P=2.69E-07）和升主动脉应变（AAo 应变）（β=0.079；P=5.19E-05）呈正相关。遗传预测的高密度脂蛋白胆固醇（HDL-C）水平与左心室径向舒张峰值应变率（LV-PDSRll）（β=0.176；P=2.89E-05）和左心室纵向舒张峰值应变率（LV-PDSRrr）（β=0.059；P=2.44E-06）呈正相关，与左心室局部壁厚度（LVRWT）呈负相关。载脂蛋白 B（ApoB）水平与 AAo 应变（β=0.076；P=1.16E-05）和 DAo 应变（β=0.065；P=2.77E-05）呈正相关。通过共定位分析发现一个共享的因果变异体，表明 ApoB 与 AAo 应变和 DAo 应变之间存在关联。敏感性分析证实了这些关联的稳健性。通过干预手段靶向脂质和载脂蛋白水平可能为 CVD 的一级预防提供新的策略。
