Association of hematopoietic mosaic loss of chromosome Y with dermatitis and eczema risk: an analysis in a large-scale prospective cohort study.

BACKGROUND

Evidence regarding the role of hematopoietic mosaic loss of chromosome Y (mLOY) in incident dermatitis and eczema (DE) risk, and its contribution to male susceptibility remains limited.

OBJECTIVE

To evaluate the associations of mLOY with incident DE and to assess whether mLOY may contribute to sex differences in DE susceptibility.

METHODS

This prospective study included 189,572 UK Biobank men free of DE at baseline, recruited between 2006 and 2010. Hematopoietic mLOY was derived from genotyping intensity data and analysed as both categorical mLOY status and continuous mLOY percentage (mLOY%). Cox proportional hazards models were used to estimate associations with incident DE. Sex susceptibility was evaluated in a 1:1 propensity score-matched male-female cohort. Genetic modification was assessed using a DE polygenic risk score (PRS), and mediation by circulating metabolites was explored in the Metabolomics analyses.

RESULTS

During follow-up, 9,608 men developed DE. In fully adjusted models, both low mLOY (8-20%) and high mLOY (>20%) were associated with increased DE risk, with the strongest association observed for high mLOY [adjusted hazard ratio (aHR) 1.44, 95% CI 1.26-1.66; P <0.001]. Compared with females, males without detectable mLOY had a similar DE risk, whereas males with low mLOY and high mLOY had progressively higher risks (aHR 1.14, 95% CI 1.07-1.21; and aHR 1.52, 95% CI 1.32-1.74, respectively), supporting a contribution of mLOY to male susceptibility. In age-mLOY discordance analyses, younger men with high mLOY showed a DE risk approaching that of older men without high mLOY, consistent with accelerated biological ageing. The greatest risk was observed in men with both high mLOY and high PRS (aHR 1.85, 95% CI 1.49-2.31; P <0.001). In metabolomic analyses, 98 circulating metabolites significantly mediated the mLOY-DE association, predominantly lipoprotein-related traits.

CONCLUSION

Hematopoietic mLOY was associated with an increased risk of incident DE and may contribute to late-life sex differences in DE susceptibility. Lipoprotein-centric mediation signals implicate modifiable metabolic pathways and support integrating mLOY status and lipid profiling into risk assessment for older men.