Dyslipidaemias is the leading risk factor of several major cardiovascular diseases (CVDs), but there is still a lack of sufficient evidence supporting a causal role of lipoprotein subspecies in CVDs. In this study, we comprehensively investigated several lipoproteins and their subspecies, as well as other metabolites, in relation to coronary heart disease (CHD), heart failure (HF) and ischemic stroke (IS) longitudinally and by Mendelian randomization (MR) leveraging NMR-measured metabolomic data from 118,012 UK Biobank participants. We found that 123, 110 and 36 analytes were longitudinally associated with myocardial infarction, HF and IS (FDR < 0.05), respectively, and 25 of those were associated with all three outcomes. MR analysis suggested that genetically predicted levels of 70, 58 and 7 analytes were associated with CHD, HF and IS (FDR < 0.05), respectively. Two analytes, ApoB/ApoA1 and M-HDL-C were associated with all three CVD outcomes in the MR analyses, and the results for M-HDL-C were concordant in both observational and MR analyses. Our results implied that the apoB/apoA1 ratio and cholesterol in medium size HDL were particularly of importance to understand the shared pathophysiology of CHD, HF and IS and thus should be further investigated for the prevention of all three CVDs.

血脂异常是几种主要心血管疾病 (CVD) 的主要危险因素，但仍缺乏足够的证据支持脂蛋白亚种在 CVD 中的因果作用。在这项研究中，我们利用 NMR 通过孟德尔随机化 (MR) 纵向全面研究了与冠心病 (CHD)、心力衰竭 (HF) 和缺血性中风 (IS) 相关的几种脂蛋白及其亚种以及其他代谢物-测量了 118,012 名英国生物银行参与者的代谢组数据。我们发现 123、110 和 36 种分析物分别与心肌梗死、HF 和 IS (FDR < 0.05) 纵向相关，其中 25 种分析物与所有三种结局相关。 MR 分析表明，70、58 和 7 种分析物的基因预测水平分别与 CHD、HF 和 IS 相关 (FDR < 0.05)。两种分析物 ApoB/ApoA1 和 M-HDL-C 与 MR 分析中的所有三种 CVD 结果相关，并且 M-HDL-C 的结果在观察分析和 MR 分析中都是一致的。我们的结果表明，中等大小 HDL 中的 apoB/apoA1 比率和胆固醇对于了解 CHD、HF 和 IS 的共同病理生理学特别重要，因此应进一步研究以预防所有三种 CVD。