Obesity-Related Metabolites are Associated with Incident Coronary Heart Disease and Respond to Metabolic and Bariatric Surgery

ObjectiveObesity is a major risk factor for coronary heart disease (CHD). This study aims to develop a metabolite signature of body mass index (BMI-MetSig) then assess its association with incident CHD and responsiveness to metabolic and bariatric surgery (MBS). Research Design and MethodsIn a case-control study of incident CHD nested within the Southern Community Cohort Study (SCCS) including 600 case-control pairs, we used elastic net regression with 10-fold cross-validation to derive the BMI-MetSig. Associations of BMI-MetSig with incident CHD was examined using conditional logistic regression in the nested case-control study. Further, in a cohort of 95 patients who received MBS, we evaluated this BMI-MetSig in association with estimated 30-year cardiovascular disease (CVD) risks, which was estimated by the American Heart Associations PREVENT equations, and examined changes of its constituent metabolites after surgery using linear mixed-effects models. ResultsIn the SCCS, the BMI-MetSig, comprising 94 metabolites, was significantly associated with incident CHD risk among all participants (OR per standard deviation [SD] increase: 1.48; 95% CI, 1.28-1.71) and across subgroups. Among MBS patients, the BMI-MetSig was significantly associated with increased estimated 30-year risks of CHD ({beta} per SD increase: 1.29; p<0.001) and other CVDs. Levels of 17 (20.0%) and 19 (22.4%) metabolites in the BMI-MetSig significantly changed 3- and 12-month post-surgery (FDR<0.10 and log2FC > 0.15), including choline and acetyl-2-aminoadipate. ConclusionsThe BMI-MetSig is associated with higher CHD incidence and estimated 30-year CVD risks and responds to MBS. BMI-MetSig may serve as a blood-based biomarker for cardiometabolic risk stratification and monitoring.