Hypertension-associated DNA methylation signatures and multi-generational epigenetic clocks in Korean adults

Hypertension is a hallmark of vascular aging; however, the epigenetic link between biological aging and blood pressure remains unclear. This epigenome-wide association study of hypertension examined 1528 Korean adults (896 normotensive, 632 hypertensive) from the Korean Genome and Epidemiology Study using the Illumina MethylationEPIC 850K array. Overall, 53 differentially methylated positions and 10 differentially methylated regions were identified, with the top region mapping to HIVEP3, an NF-kappaB signaling inhibitor. Among the twelve hallmarks of aging, only chronic inflammation showed nominal enrichment (OR = 23.13, P = 0.045); this signal was driven solely by HIVEP3 and did not retain significance after accounting for multiple hallmarks. All five epigenetic clocks spanning three generations were significantly associated with hypertension, and DunedinPACE showed the strongest statistical significance (per-standard-deviation OR = 1.51, P = 1.3 × 10^-8). Statistical mediation analysis revealed that all five clocks were consistent with mediating the age-hypertension association, with PC-GrimAge showing the largest proportion (62.2%) and DunedinPACE the most robust statistical significance (16.4%, P < 0.001). Machine-learning classification achieved an area under the curve of 0.910, with negligible improvement after the addition of epigenetic age features (+ 0.003), indicating substantial redundancy between hypertension-associated methylation sites and epigenetic age measures. Independent replication in 392 participants showed directional concordance for 64.7% of differentially methylated positions (P = 0.049). These exploratory findings indicate that hypertension-associated epigenetic changes are captured by multi-generational epigenetic clocks and may implicate inflammation-related pathways, warranting confirmation in longitudinal studies.