Data from the UK Biobank suggests that men with an accelerated loss of their Y chromosome in blood cells are more likely to develop dermatitis and eczema.
Genetics partly explains why older men and women experience dermatitis and eczema at different rates – but not in the way you might think, according to a new study.
Mosaic loss of chromosome Y (mLOY) is a phenomenon where the Y chromosome is lost from a subset of cells in a male’s body. It is known to be a genetic risk factor for common age-related diseases and reduced male longevity.
Previous studies have shown that haemopoietic mLOY influences leukocyte function and drives profibrotic signalling, leading researchers to wonder whether mLOY could be a biologically plausible yet male specific risk for dermatological conditions in older age.
New research published in the British Journal of Dermatology appears to confirm these suspicions.
Using data from the UK Biobank, Chinese researchers identified 189,572 men without dermatitis and eczema (DE) at the time of entering the population-based cohort study, with an average age of 56.6 years.
During a follow-up period of unspecified length, 9608 of the men (5.1% of the entire cohort) went on to develop DE. Compared to men who did not develop DE, the men who did were older (average age 58.2 versus 56.5 years), had a higher BMI (mean 28.3 versus 27.7kg/m2), and a greater proportion were current or former smokers (56.4 versus 49.9%).
The men in the DE group also had a greater median mLOY% (0.28 versus 0), and there were differences in the proportion of mLOY detected among participants. For men without DE, 88.3% had no detectable mLOY (i.e., <8% mLOY), 10.2% had mLOY between 8 and 20%, and 1.5% had mLOY exceeding 20%. In contrast 86.3% of men who went on to develop DE had no detectable mLOY, 11.4% had mLOY 8-20%, and 2.2% had mLOY >20%.
After accounting for the influence of socioeconomic deprivation, education level, smoking status, alcohol intake, and baseline comorbidities, men with low levels of mLOY (8-20%) were 12% more likely to develop DE compared to men without mLOY (adjusted hazard ratio 1.12, 95% confidence interval 1.19), while men with high levels of mLOY (>20%) were 44% more likely (1.44, 1.26-1.66).
“Each 10% increase in mLOY% was associated with a higher DE risk (1.12, 1.08-1.15),” the researchers wrote. “Conversely, higher [retention of the Y chromosome was] associated with substantially lower risk (0.36, 0.27-0.50). Taken together, these results indicate a robust dose-response relationship between leukocyte Y-chromosome loss and DE).”
Sex-specific patterns were also observed. After matching the men with women from the Biobank on demographic and health characteristics, men with no detectable mLOY did not display an increased risk of DE compared to women (0.99, 0.96-1.02). However, men with low mLOY and high mLOY were more likely to develop DE compared to women (1.14, 1.07-1.21 and 1.52, 1.32-1.74, respectively).
“These results demonstrate that males without detectable mLOY carry a similar DE risk to females, while increasing mLOY burden confers progressively higher risk, identifying high mLOY as a male-specific risk factor contributing to the excess DE burden in older men,” the researchers noted.
Related
The researchers went on to identify 98 metabolites that mediated the association between high levels of mLOY and DE. The mediators, each accounting for 0.6 to 2.5% of the relationship, included lipoproteins, phospholipids, LDL free cholesterol, and lactate.
“The mechanisms linking mLOY to DE remain uncertain, but emerging evidence suggests that hematopoietic mLOY is more than a passive marker and may reshape immune and profibrotic pathways,” the researchers said. “In observational human studies, mLOY in circulating monocytes or leukocytes has been associated with poorer outcomes and with profibrotic molecular signatures, including enhanced TGF-β- 2 related signaling.”
“In parallel, impaired cholesterol efflux and altered lipid handling in myeloid cells are well-established drivers of innate immune activation, with free or modified cholesterol and lipoprotein cargo engaging TLR- and inflammasome-related pathways.
“Taken together, these findings support a model in which hematopoietic mLOY is linked to systemic metabolic dysregulation, particularly lipoprotein remodelling, that may partly mediate susceptibility to DE.”
In an accompanying commentary, Josefin Bjurling (a PhD student) and Associate Professor Lars Forsberg, both from the Department of Immunology, Genetics and Pathology at Uppsala University in Sweden, said the Chinese researchers provided “compelling evidence” that the loss of chromosome Y in the blood increased the risk of developing DE in men, and that mLOY could potentially serve as a biomarker for risk stratification moving forward.
“The genetic risk of mLOY largely overlaps with markers of genomic instability implicated in susceptibility to multiple diseases. Assessing whether genetic predisposition to DE influences this association is therefore important to clarify whether mLOY is an independent risk factor or a marker of underlying genomic instability,” they wrote.
This is high praise, given Professor Forsberg led the landmark 2014 study that, for the first time, demonstrated an association between mLOY and all-cause mortality, as well as several types of cancers. Between its discovery in 1963 and the publication of the Nature Genetics paper some 50 years later, mLOY was predominantly thought to be a normal part of aging that had little clinical significance.
The researchers have suggested that prospective, longitudinal studies where mLOY is tracked over time will provide further details about the association between accelerated Y-chromosome loss and impending disease.
