■动脉和静脉心血管疾病,如冠状动脉疾病(CAD),外周动脉疾病(PAD),静脉血栓栓塞(VTE),是遗传相关的。询问潜在机制可能会阐明疾病机制。在这项研究中,我们的目的是确定(1)流行病学和(2)因果关系,代谢物和CAD之间的遗传关系,PAD,和VTE。
■我们使用了英国生物库95402名个体的代谢组学数据,排除患有心血管疾病的个体。Cox比例风险模型估计了249种代谢物与事件疾病的关联。双向2样本孟德尔随机化(MR)使用代谢物的全基因组关联汇总统计(来自英国生物银行的n=118466)估计了代谢物与结果之间的因果关系,CAD(n=184305,来自CARDIOGRAMplusC4D2015),PAD(来自百万退伍军人项目的n=243060),和VTE(来自百万退伍军人项目的n=650119)。在随后的分析中进行多变量MR。
■我们发现196、115和74个代谢物与CAD相关(P<0.001),PAD,还有VTE,分别。用MR进一步询问这些代谢物,发现94、34和9种代谢物对CAD有潜在的因果关系,PAD,还有VTE,分别。CAD和PAD共有21种代谢物,PAD和VTE共有4种代谢物。许多推定的因果代谢物包括在不同大小和脂质亚组分之间具有异质性的脂蛋白性状。小的VLDL(极低密度脂蛋白)颗粒会增加CAD的风险,而大的VLDL颗粒会降低VTE的风险。我们确定了CAD和PAD对HDLs(高密度脂蛋白)中胆固醇和甘油三酯浓度的作用方向相反。随后的敏感性分析,包括多变量MR揭示了几种代谢产物,VLDL颗粒对CAD的潜在因果效应。
■虽然常见的血管疾病与代谢组学重叠有关,MR优先考虑了特定脂蛋白种类对潜在药理靶标的作用,以最大程度地提高动脉和静脉床的益处。
UNASSIGNED: Arterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating underlying mechanisms may shed light on disease mechanisms. In this study, we aimed to identify (1) epidemiological and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE.
UNASSIGNED: We used metabolomic data from 95 402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Cox proportional-hazards models estimated the associations of 249 metabolites with incident disease. Bidirectional 2-sample Mendelian randomization (MR) estimated the causal effects between metabolites and outcomes using genome-wide association summary statistics for metabolites (n=118 466 from the UK Biobank), CAD (n=184 305 from CARDIoGRAMplusC4D 2015), PAD (n=243 060 from the Million Veterans Project), and VTE (n=650 119 from the Million Veterans Project). Multivariable MR was performed in subsequent analyses.
UNASSIGNED: We found that 196, 115, and 74 metabolites were associated (P<0.001) with CAD, PAD, and VTE, respectively. Further interrogation of these metabolites with MR revealed 94, 34, and 9 metabolites with potentially causal effects on CAD, PAD, and VTE, respectively. There were 21 metabolites common to CAD and PAD and 4 common to PAD and VTE. Many putatively causal metabolites included lipoprotein traits with heterogeneity across different sizes and lipid subfractions. Small VLDL (very-low-density lipoprotein) particles increased the risk for CAD while large VLDL particles decreased the risk for VTE. We identified opposing directions of CAD and PAD effects for cholesterol and triglyceride concentrations within HDLs (high-density lipoproteins). Subsequent sensitivity analyses including multivariable MR revealed several metabolites with robust, potentially causal effects of VLDL particles on CAD.
UNASSIGNED: While common vascular conditions are associated with overlapping metabolomic profiles, MR prioritized the role of specific lipoprotein species for potential pharmacological targets to maximize benefits in both arterial and venous beds.