Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study

Background: Myocardial infarction (MI) is a critical cardiovascular event with multifaceted etiology, involving several genetic and environmental factors. It is essential to understand the function of plasma metabolites in the development of MI and unravel its complex pathogenesis.

Methods: This study employed a bidirectional Mendelian randomization (MR) approach to investigate the causal relationships between plasma metabolites and MI risk. We used genetic instruments as proxies for plasma metabolites and MI and conducted MR analyses in both directions to assess the impact of metabolites on MI risk and vice versa. In addition, the large-scale genome-wide association studies datasets was used to identify genetic variants associated with plasma metabolite (1400 metabolites) and MI (20,917 individuals with MI and 440,906 individuals without MI) susceptibility. Inverse variance weighted was the primary method for estimating causal effects. MR estimates are expressed as beta coefficients or odds ratio (OR) with 95% CI.

Results: We identified 14 plasma metabolites associated with the occurrence of MI (P < 0.05), among which 8 plasma metabolites [propionylglycine levels (OR = 0.922, 95% CI: 0.881-0.965, P < 0.001), gamma-glutamylglycine levels (OR = 0.903, 95% CI: 0.861-0.948, P < 0.001), hexadecanedioate (C16-DC) levels (OR = 0.941, 95% CI: 0.911-0.973, P < 0.001), pentose acid levels (OR = 0.923, 95% CI: 0.877-0.972, P = 0.002), X-24546 levels (OR = 0.936, 95% CI: 0.902-0.971, P < 0.001), glycine levels (OR = 0.936, 95% CI: 0.909-0.964, P < 0.001), glycine to serine ratio (OR = 0.930, 95% CI: 0.888-0.974, P = 0.002), and mannose to trans-4-hydroxyproline ratio (OR = 0.912, 95% CI: 0.869-0.958, P < 0.001)] were correlated with a decreased risk of MI, whereas the remaining 6 plasma metabolites [1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) levels (OR = 1.051, 95% CI: 1.018-1.084, P = 0.002), behenoyl dihydrosphingomyelin (d18:0/22:0) levels (OR = 1.076, 95% CI: 1.027-1.128, P = 0.002), 1-stearoyl-2-docosahexaenoyl-GPE (18:0/22:6) levels (OR = 1.067, 95% CI: 1.027-1.109, P = 0.001), alpha-ketobutyrate levels (OR = 1.108, 95% CI: 1.041-1.180, P = 0.001), 5-acetylamino-6-formylamino-3-methyluracil levels (OR = 1.047, 95% CI: 1.019-1.076, P < 0.001), and N-acetylputrescine to (N (1) + N (8))-acetylspermidine ratio (OR = 1.045, 95% CI: 1.018-1.073, P < 0.001)] were associated with an increased risk of MI. Furthermore, we also observed that the mentioned relationships were unaffected by horizontal pleiotropy (P > 0.05). On the contrary, MI did not lead to significant alterations in the levels of the aforementioned 14 plasma metabolites (P > 0.05 for each comparison).

Conclusions: Our bidirectional MR study identified 14 plasma metabolites associated with the occurrence of MI, among which 13 plasma metabolites have not been reported previously. These findings provide valuable insights for the early diagnosis of MI and potential therapeutic targets.