Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
Medicine (Baltimore). 2024 Sep 6;103(36):e39451. doi: 10.1097/MD.0000000000039451.
Previous studies have reported correlations between metabolic factors and abdominal aortic calcification (AAC). However, the causal relationship between blood metabolites and AAC remains to be fully explored. We employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationships between 486 blood metabolites and AAC. The inverse variance weighted method was primarily utilized for MR analysis, and the MR-Egger, weighted median, and Robust Adjusted Profile Score methods were used for supplementary analysis. Sensitivity analyses were conducted using Radial MR, MR-PRESSO, Cochran Q test, MR-Egger intercept, and leave-one-out analysis to evaluate the heterogeneity and pleiotropy. Furthermore, the Steiger test and linkage disequilibrium score regression were used to assess genetic correlation and directionality. Multivariable MR analysis was performed to evaluate the direct effect of metabolites on AAC. Through rigorous screening, we identified 6 metabolites with presumed causal effects on AAC: 4-methyl-2-oxopentanoate (effect size [ES] 0.46, 95% confidence interval [CI]: 0.10-0.82), erythrose (ES -0.35, 95% CI: -0.59 to -0.11), 10-undecenoate (11:1n1) (ES 0.14, 95% CI: 0.03-0.25), 1-myristoylglycerophosphocholine (ES 0.31, 95% CI: 0.11-0.50), glycerol 2-phosphate (ES 0.20, 95% CI: 0.04-0.37), and the unidentified metabolite X-11469 (ES 0.19, 95% CI: 0.08-0.30). Multivariable MR analysis revealed that genetically predicted erythrose, 10-undecenoate, 1-myristoylglycerophosphocholine, and X-11469 could directly affect AAC independent of other metabolites. Reverse MR analysis revealed an alteration in 12 blood metabolites due to AAC, including caffeine, 1,7-dimethylurate, arachidonic acid, and 1-arachidonoylglycerophosphocholine. This study provides evidence supporting a causal relationship between metabolites and AAC. These findings help elucidate the underlying biological mechanisms of AAC and may offer insights into screening, prevention, and treatment approaches.
先前的研究报告表明代谢因素与腹主动脉钙化（AAC）之间存在关联。然而，血液代谢物与 AAC 之间的因果关系仍有待充分探索。我们采用双向两样本 Mendelian 随机化（MR）方法研究 486 种血液代谢物与 AAC 之间的潜在因果关系。主要采用逆方差加权法进行 MR 分析，并用 MR-Egger、加权中位数和稳健调整 Profile 得分法进行补充分析。采用 Radial MR、MR-PRESSO、Cochran Q 检验、MR-Egger 截距和单倍型缺失分析进行敏感性分析，以评估异质性和多效性。此外，采用 Steiger 检验和连锁不平衡得分回归来评估遗传相关性和方向性。进行多变量 MR 分析以评估代谢物对 AAC 的直接影响。通过严格筛选，我们确定了 6 种代谢物对 AAC 具有假定的因果作用：4-甲基-2-氧代戊酸（效应大小 [ES] 0.46，95%置信区间 [CI]：0.10-0.82）、赤藓糖（ES -0.35，95% CI：-0.59 至 -0.11）、10-十一碳烯酸（11:1n1）（ES 0.14，95% CI：0.03-0.25）、1-肉豆蔻酰甘油磷酸胆碱（ES 0.31，95% CI：0.11-0.50）、甘油 2-磷酸（ES 0.20，95% CI：0.04-0.37）和未鉴定的代谢物 X-11469（ES 0.19，95% CI：0.08-0.30）。多变量 MR 分析表明，遗传预测的赤藓糖、10-十一碳烯酸、1-肉豆蔻酰甘油磷酸胆碱和 X-11469 可以直接影响 AAC，而不受其他代谢物的影响。反向 MR 分析显示，由于 AAC，12 种血液代谢物发生了变化，包括咖啡因、1,7-二甲基尿酸、花生四烯酸和 1-花生四烯酰甘油磷酸胆碱。本研究提供了代谢物与 AAC 之间存在因果关系的证据。这些发现有助于阐明 AAC 的潜在生物学机制，并为筛查、预防和治疗方法提供新的思路。
