Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease

• DOI: 10.1371/journal.pgen.1004801
• Publication Date: 2014-12-11T14:01:25Z
• Authors: Andrea Ganna; Samira Salihovic; Johan Sundström; Corey D. Broeckling; Åsa K. Hedman; Patrik K. E. Magn...; Nancy L. Pedersen; Anders Larsson; Agneta Siegbahn; Mihkel Zilmer; Jessica Prenni; Johan Ärnlöv; Lars Lind; Tove Fall; Erik Ingelsson
• Keywords: Male; Coronary Disease; QH426-470; Polymorphism, Single Nucleotide; 03 medical and health sciences; 0302 clinical medicine; Genetics; Humans; Metabolomics; Longitudinal Studies; Prospective Studies; Genetic Association Studies; Aged; Gene Expression Profiling; Incidence; Klinisk medicin; Lysophosphatidylcholines; Reproducibility of Results; Public Health, Global Health, Social Medicine and Epidemiology; Folkhälsovetenskap, global hälsa och socialmedicin; Middle Aged; Public Health, Global Health and Social Medicine; 3. Good health; Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi; C-Reactive Protein; Linear Models; Monoglycerides; Female; Clinical Medicine; Biomarkers; Research Article; Follow-Up Studies

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.