Abstract Body: Introduction: Hypertension is a major global health issue linked to increased risks of stroke, cardiac, and renal disease. A family history of stroke raises the risk of hypertension, implying both genetic and environmental contributions. Genomic studies have identified single-nucleotide polymorphisms associated with blood pressure (BP); however, these account for only a fraction of its heritability, suggesting the involvement of epigenetic mechanisms like DNA methylation and histone modification.

Hypothesis: We hypothesized that epigenetic alterations, particularly DNA methylation and histone modifications, are consistently associated with hypertension in individuals with a family history of stroke.

Methods: Following PRISMA guidelines, we systematically searched PubMed and Google Scholar using terms including “hypertension,” “epigenetics,” “DNA methylation,” “histone modifications,” and “stroke family history.” Studies were screened for relevance to epigenetic markers, cohort/observational design, and reported associations with BP phenotypes. Data extraction focused on DNA methylation at CpG sites, histone modifications, and epigenetic risk scores (ERS), with emphasizing large population-based studies like the Framingham Heart Study.

Results: Of the 18 studies screened, 7 met the inclusion criteria. CpG methylation in genes regulating vascular tone and inflammation was consistently associated with elevated blood pressure. Accelerated epigenetic aging, assessed using PhenoAge and GrimAge clocks, correlated with increased cardiovascular risk. One study identified 72 differentially methylated regions accounting for up to 66.6% of systolic BP variance, suggesting a significant epigenetic contribution. Histone modifications, such as H3K27 acetylation and H3K9 methylation, were linked to vascular smooth muscle proliferation, endothelial dysfunction, and altered renin-angiotensin system, contributing to vascular remodeling and BP dysregulation. Cross-generational Mendelian randomization showed that maternal hypertension was associated with ischemic stroke risk in offspring, supporting a heritable epigenetic influence. ERS were linked to current systolic BP but did not reliably predict future hypertension.

Conclusions: This review highlights the role of epigenetic alterations in hypertension, especially in those with a family history of stroke. These findings support the potential utility of epigenetic biomarkers for early risk prediction and targeted intervention.