Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, UK.
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, UK.
Eur Heart J. 2019 Sep 7;40(34):2883-2896. doi: 10.1093/eurheartj/ehz235.
To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD).
We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10-14 to 1.0 × 10-6 (discovery) and P = 5.6 × 10-10 to 1.1 × 10-2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05).
Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis.
描述与冠状动脉或颈动脉粥样硬化相关的血清代谢特征，并随后研究其与心血管疾病（CVD）事件的相关性。
我们在来自动脉粥样硬化多民族研究（MESA）的 3867 名参与者中使用质子磁共振波谱（1H NMR）进行非靶向一维（1D）血清代谢组学分析，在来自鹿特丹和 LOLIPOP 研究的 3569 名参与者中进行了复制。通过冠状动脉钙（CAC）和颈动脉内膜中层厚度（IMT）评估动脉粥样硬化。我们使用多变量线性回归评估了 NMR 特征与动脉粥样硬化之间的相关性，同时考虑了多重比较的影响。然后，我们在 MESA 和鹿特丹的研究中检查了与动脉粥样硬化相关的代谢物与心血管疾病事件之间的相关性，并通过生物信息学分析探索了分子网络。总的来说，30 种 1H NMR 测量的代谢物与 CAC 和/或 IMT 相关，P 值为 1.3×10-14 至 1.0×10-6（发现）和 5.6×10-10 至 1.1×10-2（复制）。这些相关性在调整了传统心血管危险因素后明显减弱。与动脉粥样硬化相关的代谢物表明脂质和碳水化合物代谢、支链和芳香族氨基酸代谢以及氧化应激和炎症途径存在紊乱。对心血管疾病事件的分析显示，肌酸、肌酐和苯丙氨酸呈负相关，而甘露糖、对乙酰氨基酚葡萄糖醛酸和乳酸以及载脂蛋白 B 呈正相关（P<0.05）。
两种血管床（冠状动脉和颈动脉）之间的动脉粥样硬化相关代谢物基本一致，主要标记与已知心血管危险因素重叠的途径。我们提出了一个集成的系统网络，突出了动脉粥样硬化背后一系列相互关联的途径。
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