Department of Cardiology, The First Affiliated Hospital, Guangxi Medical University, China.
Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Disease Control and Prevention, China.
Eur J Prev Cardiol. 2021 Apr 10;28(2):227–234. doi: 10.1177/2047487319894679. Epub 2019 Dec 16.
Although many observational studies have shown an association between plasma homocysteine levels and cardiovascular diseases, controversy remains. In this study, we estimated the role of increased plasma homocysteine levels on the etiology of coronary heart disease and acute myocardial infarction.
A two-sample Mendelian randomization study on disease was conducted, i.e. "coronary heart disease" (n = 184,305) and "acute myocardial infarction" (n = 181,875). Nine single nucleotide polymorphisms, which were genome-wide significantly associated with plasma homocysteine levels in 57,644 subjects from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium genome-wide association study and were known to be associated at p < 5×10-8, were used as an instrumental variable.
None of the nine single nucleotide polymorphisms were associated with coronary heart disease or acute myocardial infarction (p > 0.05 for all). Mendelian randomization analysis revealed no causal effects of plasma homocysteine levels, either on coronary heart disease (inverse variance weighted; odds ratio = 1.015, 95% confidence interval = 0.923-1.106, p = 0.752) or on acute myocardial infarction (inverse variance weighted; odds ratio = 1.037, 95% confidence interval = 0.932-1.142, p = 0.499). The results were consistent in sensitivity analyses using the weighted median and Mendelian randomization-Egger methods, and no directional pleiotropy (p = 0.213 for coronary heart disease and p = 0.343 for acute myocardial infarction) was observed. Sensitivity analyses confirmed that plasma homocysteine levels were not significantly associated with coronary heart disease or acute myocardial infarction.
The findings from this Mendelian randomization study indicate no causal relationship between plasma homocysteine levels and coronary heart disease or acute myocardial infarction. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.
虽然许多观察性研究表明血浆同型半胱氨酸水平与心血管疾病之间存在关联，但仍存在争议。在这项研究中，我们评估了血浆同型半胱氨酸水平升高在冠心病和急性心肌梗死发病机制中的作用。
采用两样本 Mendelian 随机化研究方法，即“冠心病”（n=184305）和“急性心肌梗死”（n=181875）。使用来自 Coronary ARtery DIsease Genome wide Replication and Meta-analysis（CARDIoGRAM）加 The Coronary Artery Disease（C4D）Genetics（CARDIoGRAMplusC4D）联盟全基因组关联研究中，在 57644 名受试者中与血浆同型半胱氨酸水平具有全基因组显著关联且达到 p<5×10-8 的 9 个单核苷酸多态性作为工具变量。
在所有分析中，9 个单核苷酸多态性均与冠心病或急性心肌梗死无关（p>0.05）。Mendelian 随机化分析显示，血浆同型半胱氨酸水平对冠心病（逆方差加权；比值比=1.015，95%置信区间=0.923-1.106，p=0.752）或急性心肌梗死（逆方差加权；比值比=1.037，95%置信区间=0.932-1.142，p=0.499）均无因果关系。使用加权中位数和 Mendelian 随机化-Egger 方法进行敏感性分析的结果一致，并且未观察到方向性偏倚（冠心病 p=0.213，急性心肌梗死 p=0.343）。敏感性分析证实血浆同型半胱氨酸水平与冠心病或急性心肌梗死无显著相关性。
本 Mendelian 随机化研究结果表明，血浆同型半胱氨酸水平与冠心病或急性心肌梗死之间不存在因果关系。观察性研究的相互矛盾的结果可能是由于残余混杂或反向因果关系所致。
