Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease

• Published in: The Journal of clinical investigation Vol. 130; no. 3; pp. 1363 - 1376
• Main Authors: Poss, Annelise M., Maschek, J. Alan, Cox, James E., Hauner, Benedikt J., Hopkins, Paul N., Hunt, Steven C., Holland, William L., Summers, Scott A., Playdon, Mary C.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2020
• Subjects: Adult; Aged; Artificial intelligence; Biological markers; Biomarkers; Biomarkers - blood; Biomedical research; Biosynthesis; Cancer; Cardiovascular disease; Cardiovascular diseases; Ceramide; Ceramides; Ceramides - blood; Cholesterol; Cholesterol - blood; Clinical Medicine; Comparative analysis; Coronary artery; Coronary artery disease; Coronary Artery Disease - blood; Coronary heart disease; Coronary vessels; Diabetes; Diabetes mellitus; Diseases; Evaluation; Family medical history; Female; Heart diseases; Humans; Hypertension; Juvenile diabetes; Learning algorithms; Lipids; Low density lipoprotein; Low density lipoproteins; Machine Learning; Male; Membrane lipids; Middle Aged; Mortality; Novels; Physiological aspects; Plant lipids; Serum levels; Sphingolipids; Trans fatty acids; Triglycerides; Type 2 diabetes; Utah; Taiwan; Cardiovascular disease; Lipoproteins; Metabolism; Vascular Biology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI131838

BACKGROUNDCeramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).METHODSWe performed targeted lipidomics on serum samples from individuals with familial coronary artery disease (CAD) (n = 462) and population-based controls (n = 212) to explore the relationship between serum sphingolipids and CAD, using unbiased machine learning to identify sphingolipid species positively associated with CAD.RESULTSNearly every sphingolipid measured (n = 30 of 32) was significantly elevated in subjects with CAD compared with measurements in population controls. We generated a novel sphingolipid-inclusive CAD risk score, termed SIC, that demarcates patients with CAD independently and more effectively than conventional clinical CVD biomarkers including serum LDL cholesterol and triglycerides. This new metric comprises several minor lipids that likely serve as measures of flux through the ceramide biosynthesis pathway rather than the abundant deleterious ceramide species that are included in other ceramide-based scores.CONCLUSIONThis study validates serum ceramides as candidate biomarkers of CVD and suggests that comprehensive sphingolipid panels should be considered as measures of CVD.FUNDINGThe NIH (DK112826, DK108833, DK115824, DK116888, and DK116450); the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B); the American Diabetes Association; the American Heart Association; the Margolis Foundation; the National Cancer Institute, NIH (5R00CA218694-03); and the Huntsman Cancer Institute Cancer Center Support Grant (P30CA040214).