Chen Bohang, Wang Chuqiao, Li Wenjie
The First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China.
The Department of Endocrinology, Liaoning Health Industry Group Fukuang General Hospital, Fushun, Liaoning, China.
Front Immunol. 2024 Dec 3;15:1459465. doi: 10.3389/fimmu.2024.1459465. eCollection 2024.
Epidemiological evidence indicates that trace elements are significantly associated with cardiovascular health. However, its causality and underlying mechanisms remain unclear. Therefore, this study aimed to investigate the causal relationship between trace elements and cardiovascular disease, as well as their potential mechanism of action.
Two-sample Mendelian randomization (MR) analyses along with mediated and multivariate MR analyses were employed. These analyses utilized 13 trace elements as exposure variables and 20 cardiovascular diseases as outcome variables, with 4907 circulating plasma proteins, 1400 serum metabolites, 731 immune cell phenotypes, and 473 intestinal flora as potential mediators. The Bayesian weighted MR method was used to validate the MR results, and linkage disequilibrium score regression (LDSC) was applied to explore the genetic correlation between trace elements and cardiovascular disease.
Our findings indicated a positive or negative causal relationship between genetically predicted trace elements and cardiovascular disease. An analysis using the Bayesian weighted MR method demonstrated that our causal inference results were reliable. The results of the mediated MR analyses indicate that potassium may reduce the risk of ischemic heart disease by influencing the expression of the plasma proteins BDH2 and C1R. Vitamin B12 may increase the risk of coronary atherosclerosis and cardiovascular death by reducing the levels of VPS29 and PSME1 proteins, while vitamin C may mitigate the risk of cardiac arrest by inhibiting the expression of the TPST2 protein. In addition, potassium can reduce the risk of ischemic heart disease by lowering 4-methoxyphenyl sulfate levels. None of the instrumental variables exhibited pleiotropy in the MR analysis. A sensitivity analysis using the leave-one-out method further confirmed the robustness of our findings. LDSC results indicated a genetic correlation between multiple trace elements and various cardiovascular diseases.
This study uncovered the true causal relationship between trace elements and cardiovascular disease risk using genetic methods, and revealed the significant mediating role of specific plasma proteins and metabolites in this relationship.
流行病学证据表明微量元素与心血管健康显著相关。然而，其因果关系和潜在机制仍不清楚。因此，本研究旨在探讨微量元素与心血管疾病之间的因果关系及其潜在作用机制。
采用两样本孟德尔随机化（MR）分析以及中介和多变量MR分析。这些分析将13种微量元素作为暴露变量，20种心血管疾病作为结局变量，以4907种循环血浆蛋白、1400种血清代谢物、731种免疫细胞表型和473种肠道菌群作为潜在中介因素。使用贝叶斯加权MR方法验证MR结果，并应用连锁不平衡评分回归（LDSC）来探索微量元素与心血管疾病之间的遗传相关性。
我们的研究结果表明，基因预测的微量元素与心血管疾病之间存在正相关或负相关的因果关系。使用贝叶斯加权MR方法进行的分析表明，我们的因果推断结果是可靠的。中介MR分析结果表明，钾可能通过影响血浆蛋白BDH2和C1R的表达来降低缺血性心脏病的风险。维生素B12可能通过降低VPS29和PSME1蛋白水平增加冠状动脉粥样硬化和心血管死亡的风险，而维生素C可能通过抑制TPST2蛋白的表达减轻心脏骤停的风险。此外，钾可以通过降低4-甲氧基苯硫酸酯水平来降低缺血性心脏病的风险。在MR分析中，没有一个工具变量表现出多效性。使用留一法进行的敏感性分析进一步证实了我们研究结果的稳健性。LDSC结果表明多种微量元素与各种心血管疾病之间存在遗传相关性。
本研究利用遗传方法揭示了微量元素与心血管疾病风险之间的真实因果关系，并揭示了特定血浆蛋白和代谢物在这种关系中的重要中介作用。
