Abstract
Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18∶1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18∶2 (HR = 0.81, P-value<0.001), monoglyceride 18∶2 (MG 18∶2; HR = 1.18, P-value = 0.011) and sphingomyelin 28∶1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18∶2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C-reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18∶2. MG 18∶2 showed an enrichment (P-value = 0.002) of significant associations with CHD-associated SNPs (P-value = 1.2×10−7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18∶2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development.
Highlights
Advances in high-throughput technologies can fuel discovery of novel biomarkers for early detection and prevention of coronary heart disease (CHD)
Participants in Uppsala Longitudinal Study of Adult Men [25] (ULSAM) and PIVUS were all of the same approximate age at baseline, while TwinGene participants were of younger median age (64.7 years) and with a wider range
Since LysoPC 18:2 was the metabolite with the strongest association with incident CHD in ULSAM and in older participants from TwinGene, we extended our analysis to four additional LysoPC species to evaluate common patterns and pathways
Summary
Advances in high-throughput technologies can fuel discovery of novel biomarkers for early detection and prevention of coronary heart disease (CHD). Metabolomic profiling, or metabolomics, provides a holistic signature of biochemical activities in humans by detecting and quantifying low-weight molecules (,1,500 Da). Targeted metabolomics studies have identified several associations between metabolites and cardiovascular disease (CVD) risk [2,3] highlighting the importance of metabolic pathways in the development of atherosclerosis. The primary aim of our study was to identify novel CHD biomarkers by performing non-targeted metabolomics profiling in 3,668 individuals free of CHD at baseline from three populationbased prospective cohort studies. Our secondary aims were to delineate the underlying biological mechanisms and to evaluate clinical utility, as well as potential causal effects for those metabolites showing strong evidence of association.
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