Mosaic loss of chromosome Y, tobacco smoking, and risk of age-related lung diseases: insights from two prospective cohorts

Chenghao Weng; Yuxuan Zhao; Mingyu Song; Zilun Shao; Yuanjie Pang; Canqing Yu; Pei Pei; Ling Yang; Iona Y Millwood; Robin G Walters; Yiping Chen; Huaidong Du; Junshi Chen; Zhengming Chen; Giulio Genovese; Chikashi Terao; Jun Lv; Liming Li; Dianjianyi Sun; China Kadoorie Biobank Collaborative Group

doi:10.1183/13993003.00968-2024

Mosaic loss of chromosome Y, tobacco smoking, and risk of age-related lung diseases: insights from two prospective cohorts

Eur Respir J. 2024 Oct 10:2400968. doi: 10.1183/13993003.00968-2024. Online ahead of print.

Authors

Chenghao Weng^{1

2}, Yuxuan Zhao^{3

2}, Mingyu Song³, Zilun Shao³, Yuanjie Pang³, Canqing Yu^{3

4

5}, Pei Pei⁴, Ling Yang⁶, Iona Y Millwood⁶, Robin G Walters⁶, Yiping Chen⁶, Huaidong Du⁶, Junshi Chen⁷, Zhengming Chen⁶, Giulio Genovese^{8

9

10}, Chikashi Terao^{11

12

13}, Jun Lv^{3

4

5}, Liming Li^{3

4

5}, Dianjianyi Sun^{3

4

5}; China Kadoorie Biobank Collaborative Group

Affiliations

¹ School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
² These authors contributed equally to this work.
³ Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.
⁴ Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China.
⁵ Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing, China.
⁶ Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁷ China National Center for Food Safety Risk Assessment, Beijing, China.
⁸ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹¹ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
¹² Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
¹³ The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

PMID: 39401857
DOI: 10.1183/13993003.00968-2024

Abstract

Background: Little is known about the underlying relationship between mosaic loss of chromosome Y (mLOY), the most common chromosomal alterations in older men, and the risk of age-related lung diseases.

Methods: We included 217 780 participants from the UK Biobank and 42 859 participants from the China Kadoorie Biobank. The mLOY events were detected using the Mosaic Chromosomal Alterations pipeline. Outcomes included all lung diseases, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF). Cox proportional hazard models were fitted to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of mLOY with lung diseases in both cohorts. The combined HRs were derived from meta-analysis.

Results: Results from two cohorts showed that expanded mLOY was associated with increased risks of all lung diseases [HR (95% CI): 1.19 (1.04, 1.37)], COPD [HR (95% CI): 1.20 (1.13, 1.28)], lung cancer [HR (95% CI): 1.34 (1.21, 1.48)], and IPF [HR (95% CI): 1.34 (1.16, 1.56) in UKB]. There was evidence of positive interactions between mLOY and smoking behavior [relative excess risk due to interaction (97.5%CI)>0]. Additionally, we observed that current smokers with expanded mLOY had the highest risk of incident lung diseases in both cohorts.

Conclusion: mLOY may be a novel predictor for age-related lung diseases. For current smokers carrying mLOY, adopting quitting smoking behavior may contribute to substantially reduce their risk of incident lung diseases.