Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, People's Republic of China.
Shandong University of Traditional Chinese Medicine, Jinan, 250355, People's Republic of China.
Sci Rep. 2024 Aug 16;14(1):19034. doi: 10.1038/s41598-024-69879-2.
The development of coronary artery disease (CAD) is significantly affected by impaired endocrine and metabolic status. Under this circumstance, improved prevention and treatment of CAD may result from knowing the connection between metabolites and CAD. This study aims to delve into the causal relationship between human metabolic biomarkers and CAD by using two-sample Mendelian randomization (MR). Utilizing two-sample bidirectional MR analysis, we assessed the correlation between 1400 blood metabolites and CAD, and the metabolites data from the CLSA, encompassing 8299 participants. Metabolite analysis identified 1091 plasma metabolites and 309 ratios as instrumental variables. To evaluate the causal link between metabolites and CAD, we analyzed three datasets: ebi-a-GCST005195 (547,261 European & East Asian samples), bbj-a-159 (29,319 East Asian CAD cases & 183,134 East Asian controls), and ebi-a-GCST005194 (296,525 European & East Asian samples). To estimate causal links, we utilized the IVW method. To conduct sensitivity analysis, we used MR-Egger, Weighted Median, and MR-PRESSO. Additionally, we employed MR-Egger interception and Cochran's Q statistic to assess potential heterogeneity and pleiotropy. What's more, replication and reverse analyses were performed to verify the reliability of the results and the causal order between metabolites and disease. Furthermore, we conducted a pathway analysis to identify potential metabolic pathways. 59 blood metabolites and 27 metabolite ratios nominally associated with CAD (P < 0.05) were identified by IVW analysis method. A total of four known blood metabolites, namely beta-hydroxyisovaleroylcarnitine (OR 1.06, 95% CI 1.027-1.094, FDR 0.07), 1-palmitoyl-2-arachidonoyl (OR 1.07, 95% CI 1.029-1.110, FDR 0.09), 1-stearoyl-2- docosahexaenoyl (OR 1.07, 95% CI 1.034-1.113, FDR 0.07) and Linoleoyl-arachidonoyl-glycerol, (OR 1.07, 95% CI 1.036-1.105, FDR 0.05), and two metabolite ratios, namely spermidine to N-acetylputrescine ratio (OR 0.94, 95% CI 0.903-0.972, FDR 0.09) and benzoate to linoleoyl-arachidonoyl-glycerol ratio (OR 0.87, 95% CI 0.879-0.962, FDR 0.07), were confirmed as having a significant causal relationship with CAD, after correcting for the FDR method (p < 0. 1). A causal relationship was found to be established between beta -hydroxyisovalerylcarnitine and CAD with the validation in other two datasets. Moreover, multiple metabolic pathways were discovered to be associated with CAD. Our study supports the hypothesis that metabolites have an impact on CAD by demonstrating a causal relationship between human metabolites and CAD. This study is important for new strategies for the prevention and treatment of CAD.
冠心病（CAD）的发展受内分泌和代谢状态受损的显著影响。在这种情况下，通过了解代谢物与 CAD 之间的关系，可能会改善 CAD 的预防和治疗。本研究旨在通过两样本孟德尔随机化（MR）深入探讨人类代谢生物标志物与 CAD 之间的因果关系。利用两样本双向 MR 分析，我们评估了 1400 种血液代谢物与 CAD 之间的相关性，代谢物数据来自包含 8299 名参与者的 CLSA。代谢物分析确定了 1091 种血浆代谢物和 309 种比值作为工具变量。为了评估代谢物与 CAD 之间的因果关系，我们分析了三个数据集：ebi-a-GCST005195（欧洲和东亚 547261 个样本）、bbj-a-159（东亚 29319 例 CAD 病例和 183134 例东亚对照）和 ebi-a-GCST005194（欧洲和东亚 296525 个样本）。我们使用 IVW 方法估计因果关系。为了进行敏感性分析，我们使用了 MR-Egger、加权中位数和 MR-PRESSO。此外，我们还使用了 MR-Egger 截距和 Cochran's Q 统计量来评估潜在的异质性和多效性。此外，我们还进行了复制和反向分析，以验证结果的可靠性以及代谢物与疾病之间的因果顺序。此外，我们进行了通路分析，以确定潜在的代谢途径。通过 IVW 分析方法，确定了 59 种血液代谢物和 27 种代谢物比值与 CAD 之间存在显著关联（P < 0.05）。共有四种已知的血液代谢物，即β-羟异戊酰肉碱（OR 1.06，95%CI 1.027-1.094，FDR 0.07）、1-棕榈酰基-2-花生四烯酰基（OR 1.07，95%CI 1.029-1.110，FDR 0.09）、1-硬脂酰基-2-二十二碳六烯酰基（OR 1.07，95%CI 1.034-1.113，FDR 0.07）和亚油酰基-花生四烯酰基甘油（OR 1.07，95%CI 1.036-1.105，FDR 0.05）以及两种代谢物比值，即精脒与 N-乙酰腐胺的比值（OR 0.94，95%CI 0.903-0.972，FDR 0.09）和苯甲酸与亚油酰基-花生四烯酰基甘油的比值（OR 0.87，95%CI 0.879-0.962，FDR 0.07），在 FDR 方法校正后（p < 0.1），被确认为与 CAD 存在显著的因果关系。在另外两个数据集的验证中，发现β-羟异戊酰肉碱与 CAD 之间存在因果关系。此外，还发现了多个与 CAD 相关的代谢途径。我们的研究支持了代谢物对 CAD 有影响的假设，通过证明人类代谢物与 CAD 之间存在因果关系，为 CAD 的预防和治疗提供了新的策略。
