Faculty, Staff and Student Publications

Language

English

Publication Date

7-1-2026

Journal

American Journal of Respiratory and Critical Care Medicine

DOI

10.1093/ajrccm/aamag120

PMID

42085243

PMCID

PMC13322295

PubMedCentral® Posted Date

3-19-2026

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, Male, Aging, Cross-Sectional Studies, Aged, Pulmonary Emphysema, Chromosomes, Human, Y, Middle Aged, Mosaicism, Epigenesis, Genetic, Pulmonary Disease, Chronic Obstructive, Prospective Studies, Spirometry, Respiratory Function Tests, Y chromosome, spirometry, emphysema, aging, COPD

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