Abstract 16471: Epigenetic Analysis of Lipid Phenotypes in Liver Tissue from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study
Introduction: Epigenetic mechanisms have been implicated in the pathogenesis of many complex diseases, including cardiovascular disease. DNA methylation is one of the best known and currently the most practical epigenetic mechanism to quantify. We proposed to examine the patterns of DNA methylation in liver tissue from a unique NHLBI funded bio-repository, the Pathobiological Determinants of Youth (PDAY) cohort, to increase our understanding of the relationship between DNA methylation and regulation of plasma lipids.
Methods: The PDAY repository contains autopsy data on over 3000 young, multi-ethnic subjects ages 15-34 whose death was largely due to trauma, and includes baseline characteristics and gross atherosclerotic lesions. Differential DNA methylation proportions were identified from liver DNA between 72 PDAY subjects with hyperlipidemia (defined as non-high density lipoprotein (non-HDL) levels above the 90th percentile) and 72 age, race, and sex matched PDAY subjects without evidence of hyperlipidemia (non-HDL levels below the 25th percentile). Logistic regression analysis was performed modeling the binary outcome of non-HDL cholesterol as a function of methylation proportion controlling for chip and row.
Results: No individual probe met the strict threshold for genome-wide level significance (1 x 10-7). However, among the top 20 probes with the strongest association with non-HDL cholesterol are NR1H3 a key regulator of macrophage function, lipid homeostasis and inflammation, and MRAS, a member of the Ras family of GTPases that is a well-established GWAS hit for CAD (Table 1).
Conclusion: NR1H3 would be a plausible candidate for epigenetic DNA regulation leading to non-HDL phenotypic differences, and DNA methylation may provide more insight into the mechanism leading to the association of MRAS with CAD. Future research is required to validate these associations and provide insight into the role of epigenetic regulation of lipid homeostasis.
- © 2012 by American Heart Association, Inc.