Molecular markers of early cardiometabolic health transitions in the CARDIA study

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Cardiometabolic diseases (CMD) are a major cause of morbidity and mortality, specifically among African Americans. CMD has origins in youth, and ongoing efforts focus CMD prevention to early adulthood, before clinically overt cardiovascular disease (CVD) or its risk factors develop. We have established that (1) subclini- cal CVD is present in children and young adults and forecasts long-term adverse outcomes; (2) adverse CMD trajectories appear in early adulthood and are associated with mid-life CVD; (3) relative to Caucasians, African Americans exhibit greater cardiac hypertrophy/dysfunction in response to early worsening in CMD risk; (4) tra- ditional metabolic risk factors do not identify African Americans or Caucasians in early adulthood with high life- time CMD risk. These results imply pathophysiologic distinctions in how African Americans respond to CMD and call for more specific markers of metabolic dysregulation early in adulthood for risk stratification. In this re- gard, metabolites and extracellular RNAs (ex-RNAs) are circulating, stable, functional biomolecules that inte- grate metabolic signals across tissues relevant to CMD (hepatic, adipose, muscle, cardiac). We recently ob- served circulating ex-RNAs associated with CMD phenotypes (insulin resistance, hepatic/visceral fat) in older Caucasians in the Framingham Heart Study (FHS). Strikingly, several of these ex-RNAs from FHS were asso- ciated with insulin resistance and adverse metabolite profiles (branched chain amino acids) in children, with in silico analysis suggesting a regulatory role for ex-RNAs in metabolism. Therefore, metabolites and ex-RNAs may sensitively identify global metabolic dysregulation early in CMD. Nevertheless, African Americans and young adults remain underrepresented in studies of metabolomics and ex-RNAs in CMD/CVD, representing a novel locus of investigation for biological insights and risk stratification. Here, we extend our preliminary find- ings in the Coronary Artery Risk Development in Youth (CARDIA) study (1) to identify molecular biomarkers in young adulthood across race that reflect cardiometabolic health transitions through life; (2) to understand how these biomolecules impact long-term clinical disease, leveraging long-term follow-up and CVD/CMD outcomes in CARDIA. In ~2,400 biracial CARDIA participants (45% African American; mean age 32), we hypothesize that circulating metabolites and ex-RNAs dysregulated in early adulthood will identify individuals with poor long-term CMD/CVD risk over >20 years. We will determine metabolite profiles in early adulthood that identify individuals in adverse lifetime CMD trajectories and how they impact long-term CMD risk (e.g., adiposity, met- abolic syndrome; SA1). We will investigate how early adverse metabolite profiles impact future CVD (cardiac hypertrophy, fitness, vascular calcification, clinical outcomes; SA2). Finally, following results in FHS, we will use systems biology to understand implications of ex-RNAs on global metabolic dysfunction (SA3). Completion of this project by our uniquely qualified multidisciplinary team will provide a shared public resource to the broad scientific community for investigation of CMD and CVD in a young, biracial population at high lifetime risk.