Human Genetics Publications
Document Type
Article
Publication Date
7-1-2026
Abstract
Rationale: As the global population ages, identifying risk factors for age-related diseases, such as COPD, is crucial for public health. Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mosaicism event, but its relationship with pulmonary health remains undercharacterized. Objectives: To examine the association between mLOY and pulmonary outcomes in men. Methods: Leveraging mLOY assessment (cell fraction ≥ 5%) in over 12 000 men, including 5097 from the COPDGene Study and 7235 from six additional cohorts in the Trans-Omics for Precision Medicine program, we investigated mLOY associations with respiratory outcomes and epigenetic aging using multivariable cross-sectional, longitudinal, and prospective models. Primary outcomes included spirometry, CT-based emphysema, and epigenetic pace of aging. Results: The prevalence of mLOY increased with age. Cross-sectionally, mLOY was associated with airflow obstruction, with reduced FEV1/FVC of 0.018 [95% CI, −0.030 to −0.006] in COPDGene and 0.020 [95% CI, −0.027 to −0.013] in TOPMed. mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Longitudinally, mLOY was associated with faster FEV1 decline (∼55mL/year vs ∼38mL/year). Prospectively, mLOY was associated with higher odds of developing COPD [OR = 1.84, 95% CI, 1.10-3.07] and preserved ratio impaired spirometry (PRISm) [OR = 2.87, 95% CI, 1.09-7.56] among participants with normal lung function at baseline. Associations remained robust after adjusting for clonal hematopoiesis and telomere length. Conclusions: mLOY is associated with lower lung function, accelerated lung function decline, higher emphysema, and faster pace of aging, positioning mLOY as a potential biomarker of respiratory aging in men.
Recommended Citation
Saw, W. Y., Kim, K., Huang, Y., Yun, J. H., Ma, X., Bacon, J., ... & DeMeo, D. L. (2026). Mosaic loss of Y chromosome associates with lung function, emphysema, and epigenetic aging. American Journal of Respiratory and Critical Care Medicine, 212(7), 1483-1494. https://doi.org/10.1093/ajrccm/aamag120
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
First Page
1483
Last Page
1494
Publication Title
American Journal of Respiratory and Critical Care Medicine
DOI
10.1093/ajrccm/aamag120
Comments
© The Author(s) 2026. Published by Oxford University Press on behalf of the American Thoracic Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].