Extracellular RNAs in Relation to Cardiometabolic Risk

Extracellular RNAs (exRNAs) impact a wide range of biological processes and function to transfer genetic information between cells. In doing so, exRNAs affect cell-to-cell communications. Recent studies indicate that exRNAs are associated with a variety of diseases. Emerging data from elderly participants in the Framingham Heart Study (FHS) demonstrate that circulating levels of exRNA are correlated with several key traits including age, sex, and body mass index. Much more work is needed to determine the extent to which exRNAs are associated with a variety of clinically relevant traits across the age spectrum. We seek to measure a 665 exRNAs spanning a variety of classes in plasma from 4095 young to middle-aged adult participants in the Third Generation cohort of the FHS and to relate them to age, sex, and cardiometabolic risk factors (BMI, lipids, blood pressure, and fasting glucose) in cross-sectional analyses and to determine the relations of these exRNAs measured at baseline to serial changes in cardiometabolic risk factors during seven years of follow up. We also seek to relate exRNAs to subclinical atherosclerotic cardiovascular disease (ASCVD; assessed via multidetector CT measures of coronary artery calcium), and its progression during seven years of follow up. This grant application will establish an association of exRNAs with clinically relevant traits and diseases and will establish their utility as biomarkers of risk for cardiometabolic disease and subclinical ASCVD. To this end, we propose three aims: 1) To identify associations of exRNAs with age, sex, and cardiometabolic risk factors and subclinical ASCVD at a baseline examination, 2) To identify associations of exRNAs with longitudinal changes in cardiometabolic risk factors and subclinical ASCVD during seven years of follow up, and 3) To explore the genetic regulation of exRNAs via analysis of whole genome sequence data. We demonstrate that we have adequate power to detect associations of exRNAs with cardiometabolic risk factors and subclinical atherosclerosis at baseline and with their longitudinal change during follow up.