Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease

PLoS Genet. 2014 Dec 11;10(12):e1004801. doi: 10.1371/journal.pgen.1004801. eCollection 2014 Dec.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood*
  • C-Reactive Protein / metabolism
  • Coronary Disease / blood*
  • Coronary Disease / epidemiology*
  • Coronary Disease / genetics
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Genetic Association Studies
  • Humans
  • Incidence
  • Linear Models
  • Longitudinal Studies
  • Lysophosphatidylcholines / blood
  • Male
  • Metabolomics
  • Middle Aged
  • Monoglycerides / blood
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Reproducibility of Results
  • Risk Assessment
  • Risk Factors
  • Sphingomyelins / blood
  • Sweden

Substances

  • Biomarkers
  • Lysophosphatidylcholines
  • Monoglycerides
  • Sphingomyelins
  • C-Reactive Protein

Grant support

This study was supported by grants from Knut och Alice Wallenberg Foundation (Wallenberg Academy Fellow), European Research Council (ERC-2013-StG; grant no. 335395), Swedish Diabetes Foundation, Swedish Heart-Lung Foundation (grant no. 20120197), and Swedish Research Council (grant no. 2012-1397). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.