Impact of Y loss in blood on male atherosclerosis and cardiovascular risk

Atherosclerotic cardiovascular disease shows a marked male predominance(1–3), yet the biological basis for this disparity remains unclear. Mosaic loss of chromosome Y (LOY) in blood – a common, acquired and age associated mutation(4,5)- has been linked to mortality and major causes of death, including myocardial infarction(6,7). Experimental studies indicate that LOY in leukocytes is causally related to mortality(8) and promotes pathology across organs by impairing immunosurveillance of senescent cells(9), providing a mechanistic explanation for systemic effects of leukocyte Y loss. Whether LOY in blood contributes to atherosclerosis, however, is unknown. Here we show that LOY in blood is associated with subclinical and clinical atherosclerotic disease by analyzing two large, population-based cohorts: the Swedish CArdioPulmonary bioImage Study (SCAPIS) and the UK Biobank. SNP array–derived estimates of LOY mosaicism in blood leukocytes revealed dose-dependent associations with prevalence of coronary atherosclerosis, more extensive segment involvement, greater coronary stenosis and calcified plaques in SCAPIS. In UK Biobank, LOY was associated with greater carotid intima–media thickness, atherosclerosis, and myocardial infarction. Together, these findings point to a potential association between LOY in blood and a spectrum of atherosclerotic outcomes, offering one possible explanation for the higher cardiovascular risk observed in men.