Causality of the Metabolic Syndrome and its Ingredients on Cardiovascular Disease: A Two-sample Mendelian Randomization Analysis

OBJECTIVE: It is well-established that metabolic syndrome (MetS) and its ingredients increase the risk of cardiovascular disease (CVD). However, evidence of the causal link at the genetic level is limited. The current study explored the causal relationship between MetS and its ingredients and six types of CVDs using two-sample Mendelian randomization (MR), which may be helpful for the early prevention and screening of CVDs. METHODS: Several appropriate single-nucleotide polymorphisms (SNPs) were selected as instrumental variables for MetS. The random-effects inverse variance weighting (IVW) method was used as the dominant method. The threshold value was set at P<1.39E-03. MR-Egger and weighted median methods were utilized as additional tests to the MR analysis. Finally, methods such as Cochran's Q test were used to evaluate heterogeneity and pleiotropy. RESULTS: Analysis of data from subjects of European ancestry revealed that genetically predicted MetS has a significant causal link with myocardial infarction (MI) and heart failure (HF). Significant causal effects were found between type 2 diabetes (T2D) and ischemic stroke (IS), MI, and coronary artery disease (CAD). Hypertension was causally associated with stroke, MI, CAD, and atrial fibrillation (AF). Meanwhile, a causal association was found between obesity and MI and CAD. High-density lipoprotein cholesterol (HDL-C) was causally associated with stroke and MI. Triglyceride was causally associated with MI and CAD. DISCUSSION: This study utilized 18 publicly available genome-wide association study (GWAS) summary statistics and three commonly used MR methods. Through various sensitivity validations, the reliability was verified. The results revealed 15 significant causal relationships between MetS and its components and six types of CVDs. CONCLUSIONS: The two-sample MR study reveals causal associations between MetS and its ingredients and six types of CVDs. Thus, early prevention and management of MetS and its ingredients remain a cornerstone of CVD prevention.