title: Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.
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.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ganna
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Samira
authors.initials: S
authors.lastname: Salihovic
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sundström
authors.affiliation: Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Corey D
authors.initials: CD
authors.lastname: Broeckling
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PK
authors.lastname: Magnusson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Pedersen
authors.affiliation: Department of Medical Sciences, Biochemial structure and function, Uppsala University, Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Medical Sciences, Coagulation and inflammation science, Uppsala University, Uppsala, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Siegbahn
authors.affiliation: Department of Biochemistry, Centre of Excellence for Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Mihkel
authors.initials: M
authors.lastname: Zilmer
authors.affiliation: Proteomics and Metabolomics Facility, Colorado State University, Fort Collins, Colorado, United States of America; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Prenni
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Arnlöv
authors.affiliation: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Tove
authors.initials: T
authors.lastname: Fall
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D015994:Incidence; D016014:Linear Models; D008137:Longitudinal Studies; D008244:Lysophosphatidylcholines / Q000097:blood; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D050178:Monoglycerides / Q000097:blood; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013109:Sphingomyelins / Q000097:blood; D013548:Sweden
chemical_list: D015415:Biomarkers; D008244:Lysophosphatidylcholines; D050178:Monoglycerides; D013109:Sphingomyelins; D002097:C-Reactive Protein