Multi-omics analysis reveals new pathogenic methylation sites, genes, and potential regulatory pathways in essential hypertension

The complex pathophysiology of essential hypertension (EH) continues to pose challenges to blood control. This study investigated the association of blood DNA methylation and gene expression with EH in blood and arterial tissues to identify potential pathogenic methylation sites, genes, and mechanisms. We identified 767 methylation sites, 159 blood genes, and 111 arterial genes associated with EH. Among these, 41 genes were consistently associated with EH in the same direction in both blood and arterial tissues. Of these, eight genes (FDFT1, FES, GNL3, NME6, SLC22A5, UBA7, ULK3, and ZNF589) were annotated from the EH-relevant DNA methylation sites. Drug target analysis identified 64 compounds targeting FDFT1, FES, ULK3, and SLC22A5. Integration of summary data-based mendelian randomization (SMR) results revealed 72 and 79 significant DNA methylation-related, gene-proximal regulatory pathways associated with EH in single blood tissue and cross-tissue analyses, respectively. Notably, methylation sites of the FES significantly influenced changes in FES expression in both blood (cg03209642: bₘeSMR = -2. 199; cg05211768: bₘeSMR = -1. 613) and arterial tissue (cg06330618: bₘeSMR = -0. 572), influencing the risk of EH (FES in blood: bₑSMR = -0. 013; arterial tissues: bₑSMR = -0. 029). The eight methylated genes are associated with the risk of EH in both blood and arterial tissue. NME6, SLC22A5, GNL3 and UBA7 have been found to be associated with EH. The methylation-mediated regulation of FES may represent a potential new pathway in the blood and arterial tissues. These findings offer valuable insights for the development of EH biomarkers and therapeutic strategies.