Clin Epigenetics. 2026 Feb 27. doi: 10.1186/s13148-026-02087-z. Online ahead of print.
ABSTRACT
BACKGROUND: Peripheral artery disease (PAD) is a progressive vascular condition with high risks of limb amputation and adverse clinical outcomes. Despite advancements in revascularization techniques, risk stratification remains limited, especially in predicting long-term limb-specific complications. Epigenetic markers, such as DNA methylation, have emerged as potential tools for improving prognostication in vascular disease.
METHODS: We prospectively enrolled 133 patients with symptomatic PAD confirmed by imaging and angiography, all of whom underwent endovascular or surgical revascularization. Peripheral blood samples were collected prior to intervention, and VTRNA2-1 promoter methylation levels were quantified using bisulfite pyrosequencing. Hypomethylation was defined as methylation levels below 40%. Patients were followed for 12 months to monitor major adverse limb events (MALE), amputation, and renal outcomes. Methylation levels were compared to those of population-based controls from the Taiwan Biobank.
RESULTS: Among enrolled patients, 42.9% exhibited VTRNA2-1 hypomethylation. Hypomethylation was independently associated with increased amputation risk (odds ratio [OR] 2.19, 95% confidence interval [CI] 1.09-4.42, p = 0.035). In patients without end-stage renal disease (ESRD), hypomethylation was associated with higher rates of MALE (OR 2.78; 95% CI, 1.11-6.97; p = 0.028). Additionally, methylation levels in PAD patients were significantly lower than those in population-based controls.
CONCLUSION: VTRNA2-1 hypomethylation is associated with increased risk of limb-related complications in PAD patients, especially among those without ESRD. These findings suggest that VTRNA2-1 methylation status may serve as a promising biomarker for refining risk stratification in PAD. Further validation in external cohorts and mechanistic studies are warranted.
PMID:41761304 | DOI:10.1186/s13148-026-02087-z