Metabolomic Pattern Predicts Incident Coronary Heart Disease

Abstract

Objective: Alterations in the serum metabolome may be detectable in at-risk individuals prior to the onset of coronary heart disease (CHD). Identifying metabolomic signatures associated with CHD may provide insight into disease etiology and prevention. Approach and Results: Metabolomic profiling (chromatography-mass spectrometry) was performed in 2,232 African Americans and 1,366 European Americans from the Atherosclerosis Risk in Communities (ARIC) study. We applied Cox regression with least absolute shrinkage and selection operator (LASSO) to select metabolites associated with incident CHD. A metabolite risk score (MRS) was constructed to evaluate whether the MRS predicted CHD risk beyond traditional risk factors (TRFs). After 30 years of follow-up, we observed 633 incident CHD cases. Thirty-two metabolites were selected by LASSO to be associated with CHD, and 19 of the 32 showed significant individual associations with CHD, including a sugar substitute, erythritol. Theophylline (HR [95% CI] = 1.16 [1.09-1.25]) and gamma linolenic acid (HR [95% CI] = 0.89 [0.81-0.97]) showed the greatest positive and negative associations with CHD, respectively. A 1 SD greater standardized MRS was associated with a 1.37 fold higher risk of CHD (HR [95% CI] = 1.37 [1.27-1.47]). Adding the MRS to the TRFs significantly improved model predictive performance (30-year risk prediction: Δ C-statistic [95% CI] = 0.016 [0.008-0.024], continuous net reclassification index [95% CI] = 0.522 [0.480-0.556], integrated discrimination index [95%CI] = 0.038 [0.019-0.065]).

n-Butylamine for Improving the Efficiency of Untargeted Mass Spectrometry Analysis of Plasma Metabolite Composition

“…Successfully using metabolic profiling for the discovery and identification of biomarkers that can predict the risk of disease progression and define the early stages of diseases has been demonstrated in numerous studies [32,33,34]. For example, the use of plasma and serum metabolic signatures provided improved risk prediction of lung cancer, interstitial cystitis, prostate cancer, coronary heart disease, impaired glucose tolerance, tuberculosis, and so forth [25,30,35,36,37,38,39].…”

Physical Activity-Related Metabolites Are Associated with Mortality: Findings from the Atherosclerosis Risk in Communities (ARIC) Study

“…For each participant, the MRS was obtained by summing the ranked scores of each metabolite. The MRS was then standardized by its mean and SD and was further divided into quintiles for association analyses [ 71 ].…”

The Kidney–Gut–Muscle Axis in End-Stage Renal Disease is Similarly Represented in Older Adults

“…In addition, colonic permeability increases during aging in mice and monkeys [53,54], but studies in older adult humans have yet to be published. As mentioned in Section 1.1, Enterobacteriaceae contain genes involved in the production of IS and PCS [8], and accordingly, serum levels of these metabolites are higher in adults older than 65 y, when compared with younger subjects [55,56], and increase during aging [57], evidence that identifies IS and PCS as age-related, gut-derived uremic metabolites. When considering that IS and PCS negatively affect muscle mass and composition in cells and young mice, these data suggest a negative role for IS and PCS on muscle in older adults that do not have ESRD.…”