Mosaic loss of chromosome Y and coronary atherosclerosis in men: insights into sex differences in cardiovascular risk from the SCAPIS study

BackgroundAtherosclerosis predominantly affects men and is the underlying cause of coronary artery disease (CAD) and myocardial infarction (MI). Recent studies show that mosaic loss of chromosome Y (LOY) in blood is associated with all major causes of death, including CAD and MI. However, the relation between LOY and subclinical atherosclerosis remains unclear. This study aims to investigate associations between the male-specific LOY and atherosclerosis. MethodsTo examine associations between hematopoietic LOY and atherosclerosis prevalence, we analyzed imaging summary information and genotyping data from 30,000 participants ([~]50% men) in the Swedish CArdioPulmonary bioImage Study (SCAPIS). The level of LOY in whole blood DNA samples from 12,390 male participants was estimated from SNP-array data using established bioinformatics methods. Thereafter, men were divided into three groups based on the level of Y loss in blood: no detectable LOY, low LOY ({pound}10%), and substantial LOY (>10%). Low and substantial chromosome Y loss was modelled in multivariable adjusted logistic regression analyses to assess associations with male atherosclerosis, measured by coronary computed tomography angiography (CCTA) and carotid ultrasound. ResultsWe report that substantial LOY in blood leukocytes is associated with the prevalence of coronary atherosclerosis (OR=1.48, 95%CI=1.07-2.06, p=0.02) as well as the occurrence of substantial coronary stenosis (OR=1.56, 95% CI=1.05-2.25, p=0.02). We further show that men with substantial LOY exhibit a higher number of involved segments (OR=1.2, 95%CI=1.004-1.439, p=0.047) and an increased accumulation of calcified plaques (OR=1.56, 95%CI=1.08-2.37, p=0.02). In this dataset, the occurrence of carotid plaques was not associated with LOY after multivariable adjustment (OR=1.17, 95%CI=0.86-1.62, p=0.33). ConclusionsWe report that LOY in circulating blood leukocytes is associated with coronary atherosclerosis in men. These results contribute to understanding the male predominance in atherosclerosis and related cardiovascular outcomes. We hypothesize that LOY-driven atherosclerosis represents a mechanistic link in the previously described associations between LOY in blood leukocytes and major cardiovascular events in men.