Abstract
INTRODUCTION: Hematopoietic mosaic Loss Of Y chromosome (LOY), a condition referring to the age-related loss of Y chromosome in a subset of blood cells, is associated with shortened life expectancy and increased risk of age-related diseases in men. Despite Valvular Heart Disease (VHD) becoming more prevalent with aging, the underlying risk factors and mechanisms leading to sex-related differences in VHD remain unclear. OBJECTIVES: We aimed to investigate the association between hematopoietic LOY and incident VHD, and to assess whether LOY contributes to sex disparities in VHD. METHODS: We analysed UK Biobank participants aged ≥ 60 without prevalent VHD. The primary outcome was incident VHD, and the secondary outcomes were incident degenerative Aortic Stenosis (AS) and Mitral Regurgitation (MR). Associations between LOY and the outcomes were assessed using multivariate-adjusted Cox regression, estimating Hazard Ratios (HR) and 95 % confidence intervals (CI). RESULTS: Among 90,123 male participants, 606 (0.7 %) had LOY ≥ 40 %. Over a median follow-up of 14.1 years, a total of 7,663 VHD, 2,439 AS, and 1,997 MR cases were recorded. LOY ≥ 40 % was significantly associated with VHD (HR: 1.31, 95 % CI: 1.04-1.65), AS (HR: 1.47, 95 % CI: 1.00-2.15), and MR (HR: 1.69, 95 % CI: 1.12-2.55). Furthermore, male participants with LOY ≥ 40 % had significantly higher risk of VHD (HR: 1.93, 95 % CI: 1.47-2.51), AS (HR: 2.39, 95 % CI: 1.52-3.78) and MR (HR: 2.03, 95 % CI: 1.23-3.34) compared to matched females. CONCLUSIONS: Mosaic LOY is independently associated with increased risk of incident VHD and contributes to the observed sex differences in VHD susceptibility.