Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine On Prevention andTreatmentof Cardio-Cerebral Diseases, Hunan University of Chinese Medicine, Changsha, China.
Cardiovasc Toxicol. 2024 Apr;24(4):385-395. doi: 10.1007/s12012-024-09846-5. Epub 2024 Mar 27.
The aim of this study was to comprehensively assess the causal relationship between the overall genetic effect of circulating ApoE levels and panvascular lesions using newer genome-wide association data and two-sample bidirectional Mendelian randomization (MR) analysis. Two-way MR using single-nucleotide polymorphisms of circulating ApoE as instrumental variables was performed using the highest-priority Genome-wide association study (GWAS) data, with factor-adjusted and data-corrected statistics, to estimate causal associations between circulating ApoE levels and 10 pan-vascular diseases in > 500,000 UK Biobank participants, > 400,000 participants of Finnish ancestry, and numerous participants in a consortium of predominantly European ancestry. Meta-analysis was conducted to assess positive results. After correcting for statistical results, elevated circulating ApoE levels were shown to have a significant protective effect against Cerebral ischemia (CI) [IVW odds ratio (OR) 0.888, 95% Confidence Interval (CI): 0.823-0.958, p = 2.3 × 10], Coronary heart disease [IVW OR 0.950,95% CI: 0.924-0.976, p = 2.0 × 10] had a significant protective effect and potentially suggestive protective causality against Angina pectoris [IVW odds ratio (OR) 0.961, 95%CI: 0.931-0.991, p = 1.1 × 10]. There was a potential causal effect for increased risk of Heart failure (HF) [IVW ratio (OR) 1.040, 95%CI: 1.006-1.060, p = 1.8 × 10]. (Bonferroni threshold p < 0.0026, P < 0.05) Reverse MR analysis did not reveal significant evidence of a causal effect of PVD on changes in circulating ApoE levels. Meta-analysis increases reliability of results. Elevated circulating ApoE levels were particularly associated with an increased risk of heart failure. Elevated ApoE levels reduce the risk of cerebral ischemia, coronary heart disease, and angina pectoris, reflecting a protective effect. The possible pathophysiological role of circulating ApoE levels in the development of panvascular disease is emphasized.
本研究旨在利用最新的全基因组关联数据和双向孟德尔随机化（MR）分析，全面评估循环载脂蛋白 E 水平的整体遗传效应与泛血管病变之间的因果关系。使用循环载脂蛋白 E 的单核苷酸多态性作为工具变量进行双向 MR，使用英国生物库中超过 50 万名、芬兰血统中超过 40 万名参与者以及主要来自欧洲血统的联合研究中的众多参与者的最高优先级全基因组关联研究（GWAS）数据，采用因子调整和数据校正统计数据，估计循环载脂蛋白 E 水平与 10 种泛血管疾病之间的因果关系。进行荟萃分析以评估阳性结果。在对统计结果进行校正后，结果显示循环载脂蛋白 E 水平升高对脑缺血（CI）具有显著的保护作用[IVW 比值比（OR）0.888，95%置信区间（CI）：0.823-0.958，p=2.3×10]，冠心病[IVW OR 0.950，95%CI：0.924-0.976，p=2.0×10]对心绞痛具有显著的保护作用，并且可能具有保护作用[IVW 比值比（OR）0.961，95%CI：0.931-0.991，p=1.1×10]。心力衰竭（HF）的风险增加具有潜在的因果关系[IVW 比值比（OR）1.040，95%CI：1.006-1.060，p=1.8×10]。（Bonferroni 阈值 p<0.0026，p<0.05）反向 MR 分析未发现 PVD 对循环载脂蛋白 E 水平变化的因果作用有显著证据。荟萃分析增加了结果的可靠性。循环载脂蛋白 E 水平升高与心力衰竭风险增加尤其相关。循环载脂蛋白 E 水平升高降低了脑缺血、冠心病和心绞痛的风险，反映了保护作用。强调了循环载脂蛋白 E 水平在泛血管疾病发展中的可能病理生理学作用。
