Project Abstract:
The cumulative exposure to atherogenic lipoprotein particles, as well as the cholesterol mass carried
within them, are the primary causal factors for atherosclerosis. Since it is the cumulative exposure to
atherogenic lipoprotein particles that mediates atherosclerosis, the patterns of change in these particles over
the early adult life course are central to the development of atherosclerotic cardiovascular disease (ASCVD).
To date, the trajectories of lipoprotein particle number (LPN) and their determinants are not known. There are
greater than 200 distinct single nucleotide polymorphisms (SNPs) that are known to be associated with
cholesterol and triglyceride levels. However, in aggregate these SNPs explain only 12% of the population
variance in any of these parameters. Diet, physical activity, and obesity explain 10-30% of the variance in
cholesterol. The environmental and genetic influence on lipid concentrations, as well as the inter-individual
variation in the effects of these variables, suggest that non-sequence dependent changes in gene expression,
e.g., epigenetic modifications like DNA methylation (DNAm), may play a significant role in modulating LPN and
serum cholesterol levels and their consequences. If DNAm mediates some of the adverse LPN trajectories, it
may serve as an early marker of vulnerability to adverse lifestyle factors in terms of lipid homeostasis. Our
objective is to explore distinct trajectories of LPN across early adult life, the environmental and epigenetic
mediators of these trajectories, and the associations between these trajectories and ASCVD. Due to the
extensive phenotyping of epigenetic, anthropometric, and dietary and other lifestyle patterns across 34 years of
follow-up, serial serum sample availability, subclinical atherosclerosis measures, and assessment of ASCVD
events, the CARDIA study provides an unparalleled opportunity to understand the multifactorial and complex
factors that determine LPN-associated ASCVD risk. We plan to measure LPN in longitudinal samples from
CARDIA with NMR spectroscopy and describe the trajectories in LPN across early adult life and their
associated lifestyle factors, anthropometric characteristics, and epigenetic modifications. We will also quantify
the associations between LPN and subclinical atherosclerosis and ASCVD events. Understanding these key
mediators of LPN trajectories may help clinicians target individuals at high risk for adverse lipid homeostasis
and identify molecular targets for future therapies to reduce ASCVD risk through modulation of LPN.