Joint association of clonal hematopoiesis of indeterminate potential and mosaic loss of Y chromosome with all-cause and cardiovascular mortality in men
Y Sun, C Zhu, Y Yu, L Cai, Y Wang, X Tan, Y Lu, N Wang, F XiaAbstract
Background
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic loss of Y chromosome (mLOY) are age-related somatic genomic mutations linked to mortality, yet their joint impact remains unclear.
Purpose
We aimed to evaluate the joint associations of CHIP and mLOY with all-cause and cardiovascular-specific mortality in men.
Methods
From the UK Biobank, we enrolled 205 534 men aged 37–73 years whose CHIP and mLOY status were ascertained by whole-exome sequencing and high-density genotyping. Participants were categorized by CHIP/mLOY status and by specific CHIP driver genes. The outcomes were all-cause and cardiovascular disease (CVD) mortality. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident mortality.
Results
During a median follow-up of 15.3 years, 28,164 deaths occurred. Multivariable-adjusted Cox models showed that CHIP was associated with 37% and 20% increases in all-cause and CVD mortality, whereas mLOY was associated with 6% and 8% increases. When considering the combined status of CHIP and mLOY, men with CHIP(+)/mLOY(+) were associated with 43% higher risk of all-cause mortality (HR 1.43, 95% CI 1.31-1.57) compared to those with CHIP(-)/mLOY(-). For CVD subtypes, the association was significant for coronary heart disease mortality (HR 1.34, 1.10-1.63) but not for stroke or heart failure. Gene-specific analyses revealed that SRSF2 mutation carriers with co-occurring mLOY had the highest mortality risk (HR 3.52, 2.41-5.14). However, the presence of mLOY did not further increase mortality risk for carriers of TET2, ASXL1, or PPM1D mutations.
Conclusions
In this prospective cohort study, both CHIP and mLOY are independent risk factors for mortality in men, with the magnitude of joint risk varying substantially across specific CHIP driver genes.Figure 1Figure 2