Mosaic Loss of Chromosome Y, Smoking, and Risk of Symptomatic Peripheral Artery Disease: Insights From a Longitudinal Cohort Study

Background Mosaic loss of chromosome Y (mLOY) has been linked to several cardiovascular diseases, but its association with peripheral artery disease (PAD) remains unclear. We examined the relationship between mLOY and symptomatic PAD. Methods This longitudinal study included 217 047 men without prevalent PAD. mLOY was identified using the Mosaic Chromosomal Alterations pipeline. Incident symptomatic PAD was ascertained using International Classification of Diseases, Tenth Revision ( ICD‐10 ), and Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 codes. Cox regression was used to evaluate the association between mLOY and PAD. We also performed exploratory mediation analyses of immune‐inflammatory biomarkers, examined the joint association of mLOY and smoking, and assessed the contribution of mLOY to sex‐related PAD disparities. Results During a median follow‐up of 13.6 years, 4910 men developed symptomatic PAD. mLOY was associated with a higher risk of symptomatic PAD (hazard ratio [HR], 1.25 [95% CI, 1.17–1.33]; P <0.001), with the strongest association observed for expanded mLOY (mosaic cell fraction ≥10%) (HR, 1.35 [95% CI, 1.24–1.47]; P <0.001). Exploratory analyses suggested that several immune‐inflammatory biomarkers were statistically related to the mLOY‐PAD association. Additive‐scale interactions were observed between mLOY and former or current smoking. Compared with nonsmokers without mLOY, current smokers carrying mLOY had the highest PAD risk (HR, 4.69). Compared with matched women, men with mLOY had an ≈1.74‐fold higher PAD risk. Conclusions mLOY was associated with symptomatic PAD, independently of other risk factors. These findings provide biologically informative evidence linking mLOY to symptomatic PAD and highlight smoking cessation as an important public‐health priority in men.