Mosaic loss of chromosome Y and risks of peripheral arterial and aortic diseases: insights from a large prospective cohort study

Background Mosaic loss of chromosome Y (mLOY) is the most prevalent somatic mutation in males associated with aging and smoking. Whether mLOY contributes to the development of peripheral arterial and aortic diseases (PAAD) remains unclear. Objectives This study aims to assess the impact of mLOY on peripheral artery disease (PAD) and aortic aneurysm and dissection (AAD), its synergistic effect with smoking, as well as potential protein mediators. Methods 202,226 males from the UK Biobank with available genotyping data were analyzed. The Mosaic Chromosomal Alterations (MoChA) pipeline was used to detect mLOY. The multivariable Cox proportional hazard models were fitted to investigate the association of mLOY with incident PAD and AAD. Differential expression, weighted correlation network, and mediation analysis was performed to identify potential protein mediators. Results A total of 40,947 (20.2%) were identified as mLOY carriers. Over a median follow-up period of 13.6 years, individuals with mLOY had significantly higher risks of both PAD (adjusted hazard ratio [aHR], 1.21; 95% confidence interval [CI], 1.13-1.29) and AAD (aHR, 1.19; 95% CI, 1.10-1.28). In never-smokers, mLOY was not associated with increased risks of PAD and AAD (P for multiplicative interaction < 0.001). Smoking history and mLOY synergistically increase both PAD and AAD risks (P for additive interaction < 0.001). LCN2 and CLEC5A significantly mediated the associations between mLOY and both diseases, with mediation proportions ranging from 10.1% to 21.9% (P < 0.001). Conclusions mLOY is a novel PAAD-related risk factor. Individuals with mLOY are strongly advised to avoid or quit smoking. mLOY may participate in the pathogenesis of PAAD by inflammation.