Hypomethylation of VTRNA2-1 promoter predicts adverse outcomes in peripheral artery disease

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.

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.

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.

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.