Mosaic Loss of Y Chromosome and Risks of Peripheral Arterial and Aortic Diseases

BACKGROUND: Mosaic loss of Y chromosome (mLOY) is the most prevalent somatic mutation in males associated with aging. OBJECTIVES: This study aimed to test the association of mLOY with new-onset peripheral arterial and aortic diseases (PAAD). METHODS: Males from the UK Biobank with available genotyping data were analyzed. The Mosaic Chromosomal Alterations pipeline was used to detect mLOY. The multivariable Cox proportional hazard models were fitted to investigate the association of mLOY with incident peripheral arterial disease (PAD) and aortic aneurysm and dissection (AAD). Multiplicative and additive interaction between mLOY and smoking status on the risk of incident PAD and AAD was further evaluated. RESULTS: This study included 216,086 participants (mLOY: n = 43,458 [20.1%]). Over a median follow-up period of 13.7 years (IQR: 12.9-14.5), individuals with mLOY exhibited a significantly higher risk of both PAD (adjusted HR: 1.17; 95% CI: 1.10-1.24) and abdominal aortic aneurysm (AAA) (adjusted HR: 1.26; 95% CI: 1.14-1.38). Notably, although mLOY was not significantly associated with increased risks of either PAD or AAA among never-smokers, these associations were most pronounced in former smokers (P for multiplicative interaction <0.001). Furthermore, smoking status and mLOY synergistically increased the risk of both PAD and AAA (P for additive interaction <0.05). CONCLUSIONS: mLOY is a novel PAAD-related risk factor. Individuals with mLOY are strongly advised to avoid or quit smoking to reduce the risk of PAAD.