Genome-Wide DNA Methylation Profiling in Patients with Hypertension and Asymptomatic Intracranial Atherosclerotic Stenosis.

BACKGROUND: Hypertension is a major risk factor for intracranial atherosclerotic stenosis (ICAS), a leading cause of ischemic stroke in Asian populations. However, conventional risk factors only partially account for the pathogenesis of ICAS, underscoring the potential roles of epigenetic mechanisms. METHODS: We performed genome-wide DNA methylation profiling of 218 Chinese patients with hypertension using an Illumina Infinium Methylation EPIC 850K BeadChip. Identified differentially methylated positions (DMPs) were validated via pyrosequencing in 281 patients without asymptomatic ICAS (aICAS) who underwent a 4.7-year follow-up, among whom 79 developed new onset aICAS during follow-up. RESULTS: After quality control, 725,736 CpG sites were analyzed, identifying 28 DMPs (|Δβ| ≥ 0.06, FDR < 0.01) that were annotated to 16 genes. Interferon regulatory factor 1 (IRF1) showed significant hypermethylation at cg00255919 and cg21138405. Receiver operating characteristic curve analysis revealed that incorporating cg00255919 into conventional risk factors elevated the area under the curve (AUC) from 0.649 to 0.741 (P = 0.005). Pyrosequencing confirmed that cg00255919 hypermethylation was associated with a higher incidence of aICAS (adjusted HR = 1.99, 95% CI = 1.2-3.3). Kyoto Encyclopedia of Genes and Genomes analysis linked the DMPs to immune response pathways. CONCLUSIONS: This study identified novel methylation signatures for aICAS in patients with hypertension, highlighting IRF1 methylation as a potential biomarker for auxiliary screening.