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Circulating Metabolites and CHD Risk in Europe
Study Questions:
Are circulating metabolites associated with incident coronary heart disease (CHD), and what is their performance compared to conventional risk factors, high-sensitivity C-reactive protein (hs-CRP) and troponin (hs-Tn)?
Methods:
This is a substudy of the European multinational BiomarCaRE project. A total of 10,741 participants were selected using weighted random subsampling from the overall cohort of 70,000, including those with incident CHD (n = 2,166), and after excluding a history of myocardial infarction, stroke, heart failure, and atrial fibrillation. CHD was defined as the first fatal (n = 677) or nonfatal coronary events (n = 1,489) at follow-up. A total of 184 serum metabolites from five analytic groups (amino acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingolipids, and sugars) were quantified simultaneously using liquid chromatography and mass spectrometry. Survival analyses were done adjusting for body mass index, systolic blood pressure, antihypertensive treatment, diabetes, total cholesterol, sex, daily smoker status, study center, and age at examination.
Results:
The subcohort consisted of 39% women, with a median age of 57 years, and included 5.2% diabetics, 48% hypertensives, and 32% smokers. Median follow-up time was 9.2 (4.5-15.0) years. The authors identified 24 metabolites whose levels were negatively associated with incident CHD, which belonged to three different metabolite classes (phosphatidylcholines [PC]), amino acids, and sphingolipids). Five PCs (acyl-alkyl-PCs and diacyl-PCs) remained significant after adjusting for multiple testing. Associations were mostly consistent between men and women, did not differ with use of lipid-lowering medications, and were similar to that of traditional risk factors. The five PCs had decent discriminatory potential, with C-indices around 0.755, comparable to that of risk factors. Addition of these metabolites to a risk model incorporating clinical characteristics, hs-CRP, and hs-Tn, however, did not improve risk discrimination.
Conclusions:
Diacyl-PCs and acyk-alkyl-PCs were inversely correlated with incident CHD and showed comparable discrimination to that of traditional risk factors.
Perspective:
This is a remarkable study in its methodology and findings. It highlights the potential for metabolomics as a tool to reveal novel aspects of pathophysiology. In this case, PCs were confirmed as markers of CHD risk, enticing further study of their role in the disease process. While the authors used targeted metabolomics to measure 141 metabolites, nontargeted approaches have the potential to assess over 10,000 metabolites. The availability of large-sized cohorts such as the BiomarCaRE project and of new statistical approaches to big data open the door wide to large-scale evaluation of metabolic processes and their link to disease states, moving us one step closer to achieving the goal of precision medicine.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Hypertension, Smoking
Keywords: Amino Acids, Biogenic Amines, Biomarkers, Carnitine, Chromatography, Liquid, Coronary Disease, C-Reactive Protein, Glycerophospholipids, Hypertension, Lipids, Mass Spectrometry, Metabolic Syndrome, Metabolomics, Phosphatidylcholines, Primary Prevention, Risk Factors, Smoking, Sphingolipids, Amino Sugars, Troponin
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