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 repeti- tive 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 in- creased 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 con- firmed 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.