Independent associations of clonal hematopoiesis of indeterminate potential and mosaic Y loss with all-cause and cause-specific mortality in men

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic loss of the Y chromosome (mLOY) are age-related somatic genomic mutations linked to mortality, yet their independent and combined associations with mortality remain incompletely characterized. We analyzed 205,543 UK Biobank men with CHIP and mLOY status derived from genomic data and followed them for all-cause and cause-specific mortality. During a median follow-up of 15.3 years, 28,164 deaths occurred. In multivariable Cox models, CHIP was associated with higher all-cause mortality (HR 1.34, 95% CI 1.28–1.41), whereas mLOY showed a weaker association (HR 1.04, 95% CI 1.01–1.06). Men with both CHIP and mLOY had the highest absolute mortality risk (HR 1.39, 95% CI 1.27–1.52), but formal tests did not support statistically significant additive or multiplicative interaction. Similar patterns were observed across major cause-specific outcomes including cardiovascular disease mortality, cancer mortality, and respiratory mortality. Exploratory gene-specific analyses suggested heterogeneity by CHIP driver gene, with SRSF2 carriers with co-occurring mLOY showing the largest mortality estimate, although this small-subgroup finding requires replication. These findings support independent associations of CHIP and mLOY with mortality in men, while providing no clear evidence for synergistic interaction.