A stratified study of human blood metabolites and coronary artery diseases-A Mendelian randomization study.

Background and aims: Metabolic dysregulation is closely associated with coronary artery diseases (CAD). Exploring the relationship between metabolites and CAD is helpful in identifying changes in energy metabolism during disease progression.

Methods and results: We use Mendelian Randomization (MR) analysis to assess the relationships between 275 serum metabolites and CAD such as angina pectoris, post-myocardial infarction complications, coronary atherosclerosis, myocardial infarction (MI), and unstable angina pectoris (UA). The inverse variance-weighted method (IVW) served as the primary approach for causal analysis, with MR-Egger and weighted median (WM) as supplementary methods. Sensitivity analyses were conducted to assess heterogeneity and multiple effects. We also analyzed potentially related metabolic pathways.We identified causal relationships between 42 known metabolites and CAD. Among them, the genetic susceptibility to elevated levels of amino acid Isobutyrylcarnitine is associated with an increased risk of coronary artery atherosclerosis; but it provides protection against the development of MI. Genetic susceptibility to elevated levels of fatty acids Stearate, Caprylate is associated with higher risk of angina pectoris, while Threonate has a protective effect in the development of angina; Stearate is associated with an increased risk of UA, whereas higher levels of the lipids Choline, 1-arachidonoylglycerophosphoinositol∗, Hexadecanedioate, Tetradecanedioate play a protective role in UA.Metabolic pathway analysis identified 6 pathways that may be associated with CAD.

Conclusion: We identified causal relationships between 42 serum metabolites and CAD. Specifically, changes in metabolites such as Isobutyrylcarnitine, Caprylate, and Stearate were associated with risks of CAD. These findings provide new insights into the metabolic mechanisms of CAD.