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^–3], Coronary heart disease [IVW OR 0.950,95% CI: 0.924–0.976, p = 2.0 × 10^–4] 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^–2]. 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^–2]. (Bonferroni threshold p < 0.0026, P_FDR < 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.

本研究的目的是利用更新的全基因组关联数据和两样本双向孟德尔随机化 (MR) 分析，全面评估循环 ApoE 水平的总体遗传效应与全血管病变之间的因果关系。使用最高优先级全基因组关联研究 (GWAS) 数据进行双向 MR，使用循环 ApoE 的单核苷酸多态性作为工具变量，并进行因子调整和数据校正统计，以估计循环 ApoE 水平之间的因果关联以及超过 500,000 名英国生物银行参与者、> 400,000 名芬兰血统参与者以及以欧洲血统为主的联盟中的众多参与者的 10 种全血管疾病。进行荟萃分析以评估阳性结果。校正统计结果后，循环 ApoE 水平升高对脑缺血 (CI) 具有显着的保护作用 [IVW 比值比 (OR) 0.888，95% 置信区间 (CI)：0.823–0.958，p  =  2.3 × 10 ^–3 ]，冠心病 [IVW OR 0.950，95% CI：0.924–0.976，  p  = 2.0 × 10 ^–4 ] 对心绞痛具有显着的保护作用和潜在的提示性保护因果关系 [IVW 比值比 (OR) 0.961， 95%CI：0.931–0.991，  p  = 1.1 × 10 ^–2 ]。心力衰竭 (HF) 风险增加存在潜在因果效应 [IVW 比 (OR) 1.040，95%CI：1.006–1.060 ，p  = 1.8 × 10 ^–2 ]。 （Bonferroni 阈值p  < 0.0026，  P _FDR  < 0.05）反向 MR 分析没有揭示 PVD ​​对循环 ApoE 水平变化的因果影响的显着证据。荟萃分析提高了结果的可靠性。循环 ApoE 水平升高与心力衰竭风险增加尤其相关。 ApoE水平升高可降低脑缺血、冠心病和心绞痛的风险，体现出保护作用。强调了循环 ApoE 水平在全血管疾病发展中可能的病理生理学作用。