Atherosclerosis. 2026 Jul 25;420:121859. doi: 10.1016/j.atherosclerosis.2026.121859. Online ahead of print.
ABSTRACT
BACKGROUND: Mosaic loss of chromosome Y (mLOY) is the most common acquired somatic mutation in men and has been linked to multiple age-related diseases, including cardiovascular diseases. However, its association with symptomatic peripheral artery disease (PAD) remains poorly understood. We aimed to investigate the relationship between hematopoietic mLOY and incident symptomatic PAD in a large population-based male cohort.
METHODS: We conducted a longitudinal cohort study including 171 698 male participants from the UK Biobank who were free of PAD history. mLOY was assessed using leukocyte-derived genotyping data and modelled separately in three forms: binary (No/Yes), three level (No/Moderate/Substantial), and continuous (per 1-SD increase). Cox proportional-hazards models were used to analyze the association between mLOY and incident symptomatic PAD. Restricted cubic spline models were applied to evaluate nonlinear relationships. We also examined the joint associations and potential interactions between mLOY and genetic susceptibility (PAD polygenic risk score), smoking status, clonal hematopoiesis of indeterminate potential (CHIP), diabetes and estimated glomerular filtration rate (eGFR).
RESULTS: During a median follow-up of 15.3 years, 3785 participants developed symptomatic PAD. In fully adjusted Cox models, each SD increase in mLOY percentage was associated with 5% increased risk of incident symptomatic PAD (HR 1.05, 95% CI 1.02-1.07). Similarly, mLOY defined as ≥10% mLOY was associated with 37% increased risk of symptomatic PAD (HR 1.37, 95% CI 1.18-1.60). No statistically significant interactions were observed between mLOY and PAD genetic susceptibility, smoking status, CHIP status, or eGFR (all P for interaction >0.05). However, a significant interaction was observed between mLOY and diabetes status (P for interaction = 0.013), with a stronger association observed among participants without diabetes.
CONCLUSIONS: Hematopoietic mLOY is associated with an increased risk of incident symptomatic PAD in men, independent of traditional cardiovascular risk factors. Assessement of mLOY status may therefore have the potential to improve PAD risk stratification and identify high-risk individuals who would benefit most from early lifestyle modifications and preventive pharamacological treatments.
PMID:42508147 | DOI:10.1016/j.atherosclerosis.2026.121859
