Predictive metabolites for incident myocardial infarction: a two-step meta-analysis of individual patient data from six cohorts comprising 7897 individuals from the COnsortium of METabolomics Studies

Abstract

Aims Myocardial infarction (MI) is a major cause of death and disability worldwide. Most metabolomics studies investigating metabolites predicting MI are limited by the participant number and/or the demographic diversity. We sought to identify biomarkers of incident MI in the Consortium of Metabolomics Studies (COMETS). Methods and Results We included 7,897 individuals aged on average 66 years from six intercontinental cohorts with blood metabolomic profiling (n = 1,428 metabolites, of which 168 were present in at least 3 cohorts with over 80% prevalence) and MI information (1,373 cases). We performed a two-stage Individual Patients Data meta-analysis. We first assessed the associations between circulating metabolites and incident MI for each cohort adjusting for traditional risk factors, and then performed a fixed effect inverse-variance meta-analysis to pull the results together. Finally, we conducted a pathway enrichment analysis to identify potential pathways linked to MI. On meta-analysis, 56 metabolites including 21 lipids and 17 amino acids were associated with incident MI after adjusting for multiple testing (false discovery rate, FDR < 0.05), and 10 were novel. The largest increased risk was observed for the carbohydrate mannitol/sorbitol (HR [95% CI] = 1.40[1.26-1.56], p-value < 0.001), whereas the largest decrease in risk was found for glutamine (HR [95% CI] = 0.74[0.67-0.82], p-value < 0.001). Moreover, the identified metabolites were significantly enriched (corrected p-value < 0.05) in pathways previously linked with cardiovascular diseases, including aminoacyl-tRNA biosynthesis. Conclusions In the most comprehensive metabolomics study of incident MI to date, 10 novel metabolites were associated with MI. Metabolite profiles might help to identify high-risk individuals before disease onset. Further research is needed to fully understand the mechanisms of action and elaborate pathway findings. Translational Perspective In the largest meta-analyses covering six international cohorts, we identify 10 novel and 46 known metabolites associated with incident MI, that can be used to identify at-risk individuals before disease onset. Our results improve our understanding of the molecular changes that take place in MI development and provide potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.

From multi-omics approaches to personalized medicine in myocardial infarction

“…Metabolomics studies have identified several dysregulated metabolites during MI, including lipids, amino acids, energy metabolites, and oxidative stress markers (189)(190)(191). Research has revealed notable distinctions in metabolite profiles between patients with MI and healthy individuals or other populations (192,193). Some metabolites, such as 12,13-diHOME, noradrenaline, tryptophan, and cysteic acid, were significantly elevated in patients with MI, while some antioxidants like glutathione were decreased (194)(195)(196).…”

“…Research has revealed notable distinctions in metabolite profiles between patients with MI and healthy individuals or other populations ( 192 , 193 ). Some metabolites, such as 12,13-diHOME, noradrenaline, tryptophan, and cysteic acid, were significantly elevated in patients with MI, while some antioxidants like glutathione were decreased ( 194 – 196 ).…”

Interplay Between Plasma Glycine and Branched-Chain Amino Acids Contributes to the Development of Hypertension and Coronary Heart Disease

“…This is in line with other prospective and MR studies demonstrating potentially harmful effects of higher plasma BCAA levels, as well as lower plasma glycine levels on the development of hypertension, myocardial infarction, and coronary heart disease (CHD). [17][18][19][20][21] Proinflammatory and pro-oxidant effects of tBCAAs, as opposed to the potentially counteracting effects of glycine, might provide an explanation for these associations. [22][23][24] Given the fact that plasma metabolites, including amino acids, form a complex network of mutual relationships and participate in numerous biochemical cycles, 25 analyzing their ratios may provide novel information on the genetic determinants of particular metabolites and their shared biology, together with links to the disease.…”

“…This is in line with other prospective and MR studies demonstrating potentially harmful effects of higher plasma BCAA levels, as well as lower plasma glycine levels on the development of hypertension, myocardial infarction, and coronary heart disease (CHD). 17 – 21 Proinflammatory and pro-oxidant effects of tBCAAs, as opposed to the potentially counteracting effects of glycine, might provide an explanation for these associations. 22 – 24 …”