Abstract P192: Metabolomic Profiles Associated with Coronary Heart Disease in Women

Abstract

Background: Prior studies of metabolomic profiles and coronary heart disease (CHD) have been limited by relatively small case numbers and scant data in women. Methods: The discovery set examined 371 metabolites in 400 confirmed, incident CHD cases and 400 controls (frequency matched on age, race/ethnicity, hysterectomy status and time of enrollment) in the Women’s Health Initiative Observational Study (WHI-OS). All selected metabolites were validated in a separate set of 394 cases and 397 matched controls drawn from the placebo arms of the WHI Hormone Therapy trials and the WHI-OS. Discovery used 4 methods: false-discovery rate (FDR) adjusted logistic regression for individual metabolites, permutation corrected least absolute shrinkage and selection operator (LASSO) algorithms, sparse partial least squares discriminant analysis (PLS-DA) algorithms, and random forest algorithms. Each method was performed with matching factors only and with matching plus both medication use (aspirin, statins, anti-diabetics and anti-hypertensives) and traditional CHD risk factors (smoking, systolic blood pressure, diabetes, total and HDL cholesterol). Replication in the validation set was defined as a logistic regression coefficient of p<0.05 for the metabolites selected by 3 or 4 methods (tier 1), or a FDR adjusted p<0.05 for metabolites selected by only 1 or 2 methods (tier 2). Results: Sixty-seven metabolites were selected in the discovery data set (30 tier 1 and 37 tier 2). Twenty-six successfully replicated in the validation data set (21 tier 1 and 5 tier 2), with 25 significant with adjusting for matching factors only and 11 significant after additionally adjusting for medications and CHD risk factors. Validated metabolites included amino acids, sugars, nucleosides, eicosanoids, plasmologens, polyunsaturated phospholipids and highly saturated triglycerides. These include novel metabolites as well as metabolites such as glutamate/glutamine, which have been shown in other populations. Conclusions: Multiple metabolites in important physiological pathways with robust associations for risk of CHD in women were identified and replicated. These results may offer insights into biological mechanisms of CHD as well as identify potential markers of risk.