Abstract 3196: High Heritabilities of Serum Metabolites and Differential Metabolomic Profiles in Families Burdened with Early Onset Coronary Artery Disease
Introduction: Metabolomic profiling of small-molecule metabolites holds promise for integrating genetic and biochemical data to give a more complete picture of human systems biology. Profiles can predict presence of CAD, a complex disease with a known genetic basis. However, the genetic basis of these profiles has not been established. We hypothesized that metabolites are heritable in families burdened with CAD.
Methods: We identified five families from the GENECARD study of early-onset CAD. Although they share a high genetic propensity for CAD, other clinical characteristics were distinct among the families (metabolic syndrome, myocardial infarction, etc.). Blood was collected on family members with CAD and unaffected offspring (N=0 members in 5 families; 20 with CAD). Gas chromatography/mass spectrometry (MS) and tandem MS with isotope-labeled internal standards were used for targeted quantitative measurements of ~60 metabolites (free fatty acids, acylcarnitines, amino acids, conventional metabolites (lipids, glucose, ketones), CRP). Variance components using SOLAR was used to calculate heritabilities (h2).
Results: Multiple metabolites showed high heritabilities. Among acylcarnitines, C18s (steroyl, oleyl, linoleyl) and C16 (palmitoyl) were highly heritable (h2 0.42– 0.63, p<0.002), as were C5 (h2 0.35, p=0.007) and C2 (h2 0.63, p=0.0003), reflecting end-products of glucose, amino acid, and fatty acid catabolism. Among amino acids, alanine, serine, proline, valine, leucine/isoleucine, methionine, glutamic acid/glutamine, ornithine and arginine were heritable (h2 0.33 − 0.88, p=0.02 − 9E−13). Consistent with published results, CRP showed high h2 (0.56, p=0.008), as did conventional metabolites (0.34 0.57, p=0.02 −0.0002), with levels recapitulating clinical characteristics of the families.
Conclusions: We found strong heritabilities of metabolites in families with a common, high propensity for early-onset CAD, but that otherwise exhibit diverse clinical characteristics. Since this diversity includes traditional biomarkers of CAD (HDL, triglycerides, CRP), our study provides a new, and more comprehensive, set of heritable markers that may be useful in defining common and diverse mechanisms for CAD pathogenesis.