Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, China.
Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.
Clin Cardiol. 2019 Oct;42(10):934-941. doi: 10.1002/clc.23243. Epub 2019 Jul 30.
We aim to discover whether HbA1c affects incident cardiovascular disease (CVD) through regulating endogenous metabolites.
Totally, 2019 plasma samples were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Logistic regression and linear regression were used to screen metabolites which were associated with both CVD and HbA1c. The VanderWeele's mediation approach was performed to assess the direct effect and indirect effect (IE) in the counterfactual model. Forty-eight metabolites showed an association with both HbA1c and CVD risk. Forty-four of the 48 metabolites worked as mediators mediated in HbA1c's effect on CVD (odds ratio [OR] from 0.997 to 6.098, false discovery rate q < 0.05, mediated proportion from 0.4% to 85.4%). Pathway enrichment analysis indicated that different metabolic pathway showed significant IE (butanoate metabolism OR = 1.058, mediated proportion = 16.0%; alanine, aspartate and glutamate metabolism OR = 1.082, mediated proportion = 21.8%; TCA (citric acid) cycle metabolism OR = 1.048, mediated proportion = 13.8%; phenylalanine metabolism OR = 1.067, mediated proportion = 18.4%; glycerophospholipid metabolism OR = 3.007, mediated proportion = 82.2%; all the P < .01).
Our findings suggest that metabolites mediate the effect of HbA1c on incident CVD and provide a new study sight into pathogenesis of CVD.
我们旨在通过调节内源性代谢物来发现 HbA1c 是否会影响心血管疾病（CVD）的发生。
总共分析了 2019 个血浆样本，采用液相色谱-四极杆飞行时间质谱法。使用逻辑回归和线性回归筛选与 CVD 和 HbA1c 均相关的代谢物。在反事实模型中采用 VanderWeele 中介分析方法来评估直接效应和间接效应（IE）。有 48 种代谢物与 HbA1c 和 CVD 风险均相关。48 种代谢物中有 44 种作为 HbA1c 对 CVD 影响的中介物（比值比 [OR] 从 0.997 到 6.098，假发现率 q < 0.05，中介比例从 0.4%到 85.4%）。通路富集分析表明，不同代谢通路的 IE 具有显著差异（丁酸代谢 OR = 1.058，中介比例 = 16.0%；丙氨酸、天冬氨酸和谷氨酸代谢 OR = 1.082，中介比例 = 21.8%；TCA（柠檬酸）循环代谢 OR = 1.048，中介比例 = 13.8%；苯丙氨酸代谢 OR = 1.067，中介比例 = 18.4%；甘油磷脂代谢 OR = 3.007，中介比例 = 82.2%；所有 P <.01）。
我们的研究结果表明代谢物介导了 HbA1c 对 CVD 发生的影响，并为 CVD 发病机制提供了新的研究视角。
