Accelerated epigenetic age in hypertension: a systematic review and meta-analysis

Chronological age is a well-established risk factor for Hypertension (HTN), yet while biological ageing markers such as epigenetic age acceleration (EAA), have been associated with HTN, findings are inconsistent. This study aimed to conduct a systematic review and meta-analysis to evaluate the association between EAA, HTN and blood pressure (BP) to provide an understanding of the role of EAA in HTN development and progression. Six databases were searched, and studies which reported associations between DNA and HTN, and/or BP were included. Functional enrichment analysis was conducted using DAVID and STRING to elucidate underlying molecular pathways. From 4334 studies, 165 met the inclusion criteria. Qualitative analysis indicated that 17.0% of studies reporting global methylation and 49.1% of studies reporting gene-specific methylation demonstrated significant associations with HTN and/or BP. A random effects meta-analysis of 16,136 participants from 8 studies using three epigenetic clock algorithms demonstrated that HTN was associated with increased EAA (β: 0.29, 95%Cl: 0.15-0.43; P < 0.0001). All three individual epigenetic clocks demonstrated a positive association between clinically measured HTN and EAA (Horvath β: 0.33, 95%Cl: 0.08-0.58, P = 0.010; Hannum β: 0.64, 95%Cl: 0.09-1.20; PhenoAge β: 1.21, 95%Cl: 0.56-1.86), whereas this relationship was not clear when using self-reported HTN. This study is the first to systematically demonstrate that HTN is associated with EAA. We recommend the use of clinically measured over self-reported HTN in appropriately powered studies of epigenetic age to obtain an accurate understanding of BP regulation/HTN on the epigenome, supporting pathways to translation and development of novel therapeutic targets for HTN.