Repetitive element DNA methylation and circulating endothelial and inflammation markers in the VA normative aging study

Background: Lower blood DNA methylation has been associated with atherosclerosis and high cardiovascular risk. Mechanisms linking DNA hypomethylation to increased cardiovascular risk are still largely unknown. In a population of community-dwelling elderly individuals, we evaluated whether DNA methylation in LINE-1 repetitive element, heavily methylated sequences dispersed throughout the human genome, was associated with circulating Vascular Cell Adhesion Molecule-1 (VCAM-1), Inter-Cellular Adhesion Molecule-1 (ICAM-1) and C-reactive protein (CRP). Methods and results: We measured LINE-1 methylation by bisulfite PCR-Pyrosequencing on 742 blood DNA samples from male participants in the Boston area Normative Aging Study (mean age = 74.8 years). Mean serum VCAM-1 increased progressively in association with LINE-1 hypomethylation (from 975.2 to 1063.4 ng/ml in the highest vs. lowest methylation quintiles; p-trend = 0.004). The association between VCAM-1 and LINE-1 hypomethylation was significant in individuals without ischemic heart disease or stroke (n = 480; p = 0.001), but not in those with prevalent disease (n = 262; p = 0.57). Serum ICAM-1 and CRP were not associated with LINE-1 methylation (p-trend = >0.25). All results were confirmed by multivariable analyses adjusting for age, BMI, smoking, pack-years and ischemic heart disease/stroke. Conclusions: LINE-1 element hypomethylation is associated with higher serum VCAM-1. Our data provide new insights into epigenetic events that may accompany the development of cardiovascular disease