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Background <p>Mosaic chromosomal alterations (mCAs) served as a novel indicator of genomic aging. We aimed to investigate the association of expanded mCAs (cell fraction ≥ 10%) with all-cause and cause-specific mortality, and to examine the joint effect of expanded mCAs and frailty index (FI), an indicator of phenotypic aging, on mortality in two large prospective cohorts.</p> Methods <p>A total of 100,237 participants in the China Kadoorie Biobank (CKB) and 456,283 participants in the UK Biobank (UKB) were included, followed till Dec 31, 2023, and Nov 30, 2022, respectively. MoChA pipeline was used to detect expanded mCAs events and the subtypes. FIs were calculated using previously validated equations, with 28 items included in the CKB and 49 items in the UKB, and categorized participants into three groups: robust, prefrail, and frail. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to examine the associations of the expanded mCAs and joint categories of frailty-mCAs with all-cause and cause-specific mortality by using Cox proportional hazards models. The combined effect values of two cohorts were estimated using random-effects models by meta-analysis.</p> Results <p>The prevalence of expanded mCAs in the CKB and UKB was 2.2% and 3.4%, respectively. After a median follow-up of 17.2&#xa0;years in the CKB and 13.7&#xa0;years in the UKB, expanded mCAs carriers had a higher risk of all-cause (HRs [95% CIs]: 1.20 [1.16, 1.24]) and risks of cause-specific mortality (HRs [95% CIs]: 1.27 [1.21, 1.34], 1.13 [1.02, 1.25], and 1.24 [1.12, 1.37] for death from cancers, circulatory diseases, and respiratory diseases, respectively). Such associations largely did not overlap with FI, especially for all-cause and cancer mortality. Joint analyses revealed that individuals with lower frailty level but with expanded mCAs had a comparable and even higher risk of cancer mortality compared to those with higher frailty level but without mCAs. Similar pattern was also found in terms of adjusted 10-year cancer mortality rates.</p> Conclusions <p>Our findings suggested that expanded mCAs were significantly associated with all-cause and cause-specific deaths and could serve as a complement to the FI in providing a more comprehensive perspective on mortality risk, especially for cancer mortality.</p>

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Expanded mosaic chromosomal alterations, frailty, and risks of all-cause and cause-specific mortality among Chinese and the UK adults: evidence from two prospective cohorts

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  • 发表日期：

    2025年11月11日

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  • Mingyu Song,
  • Zilun Shao,
  • Yuting Han,
  • Yuxuan Zhao,
  • Jun Lv,
  • Canqing Yu,
  • Pei Pei,
  • Ling Yang,
  • Iona Y. Millwood,
  • Robin G. Walters,
  • Yiping Chen,
  • Huaidong Du,
  • Xiaoming Yang,
  • Mengwei Wang,
  • Junshi Chen,
  • Zhengming Chen,
  • Giulio Genovese,
  • Chikashi Terao,
  • Liming Li,
  • Dianjianyi Sun,
  • Robert Clarke,
  • Rory Collins,
  • Richard Peto,
  • Robin Walters,
  • Daniel Avery,
  • Maxim Barnard,
  • Derrick Bennett,
  • Ruth Boxall,
  • Ka Hung Chan,
  • Charlotte Clarke,
  • Johnathan Clarke,
  • Ahmed Edris Mohamed,
  • Hannah Fry,
  • Simon Gilbert,
  • Pek Kei Im,
  • Andri Iona,
  • Maria Kakkoura,
  • Christiana Kartsonaki,
  • Kshitij Kolhe,
  • Hubert Lam,
  • Kuang Lin,
  • James Liu,
  • Mohsen Mazidi,
  • Iona Millwood,
  • Sam Morris,
  • Qunhua Nie,
  • Alfred Pozarickij,
  • Maryam Rahmati,
  • Paul Ryder,
  • Dan Schmidt,
  • Becky Stevens,
  • Iain Turnbull,
  • Baihan Wang,
  • Lin Wang,
  • Neil Wright,
  • Pang Yao,
  • Yuanjie Pang,
  • Can Hou,
  • Qingmei Xia,
  • Chao Liu,
  • Lang Pan,
  • Xiao Han,
  • Honglu Bian,
  • Xinxin Chen,
  • Zengchang Pang,
  • Ruqin Gao,
  • Shanpeng Li,
  • Haiping Duan,
  • Shaojie Wang,
  • Yongmei Liu,
  • Ranran Du,
  • Liang Cheng,
  • Xiaocao Tian,
  • Hua Zhang,
  • Dan Hu,
  • Xiaoyan Zheng,
  • Yujie Wang,
  • Wei Sun,
  • Shichun Yan,
  • Xiaoming Cui,
  • Chi Wang,
  • Zhenyuan Wu,
  • Lishun Zhai,
  • Zhaoxi Pang,
  • Shiwen Dong,
  • Huiming Luo,
  • Jinyan Chen,
  • Bin He,
  • Dingwei Sun,
  • Xingren Wang,
  • Tingting Ou,
  • Xiangyang Zheng,
  • Dewei Zheng,
  • Shuai Yang,
  • Yilei Li,
  • Lihui Li,
  • Xingjiao Chen,
  • Jinyi Zhou,
  • Ran Tao,
  • Jian Su,
  • Xikang Fan,
  • Zongming Cheng,
  • Yuxiao Huang,
  • Yan Lu,
  • Yujie Hua,
  • Li Xing,
  • Shuxian Wang,
  • Jianrong Jin,
  • Juping Ma,
  • Jinchao Liu,
  • Kaifei Zhu,
  • Hongfu Ren,
  • Xingfeng Shen,
  • Ge Zhong,
  • Wei Mao,
  • Zhenzhen Lu,
  • Ling He,
  • Lifang Zhou,
  • Changping Xie,
  • Jian Lan,
  • Tingping Zhu,
  • Jinxue Tan,
  • Liuping Wei,
  • Liyuan Zhou,
  • Sisi Wang,
  • Xianping Wu,
  • Ningmei Zhang,
  • Xiaofang Chen,
  • Xiaoyu Chang,
  • Zhuo Wang,
  • Yujin He,
  • Mingqiang Yuan,
  • Xia Wu,
  • Xiaofang Chen,
  • Zhaodong Wang,
  • Qiang Sun,
  • Yang Lin,
  • Faqing Chen,
  • Xiaolan Ren,
  • Lijun Chang,
  • Feiming Zhong,
  • Jianjun Feng,
  • Weijie Hu,
  • Xiaofang Zhang,
  • Yalin Chen,
  • Fei Wang,
  • Jun Wang,
  • Linqi Diao,
  • Wanshen Guo,
  • Zhiwei Han,
  • Dongyang Zhao,
  • Dengjun Zhu,
  • Kai Kang,
  • Shixian Feng,
  • Huizi Tian,
  • Yali Yan,
  • Bing Han,
  • Li Gao,
  • Shaofang Li,
  • Huafei Feng,
  • Wei Tang,
  • Xiaolin Li,
  • Huarong Sun,
  • Xiaocong Zhao,
  • Ying Li,
  • Chen Hu,
  • Pan He,
  • Xukui Zhang,
  • Yuanyuan Jin,
  • Hesheng Zhang,
  • Min Yu,
  • Ruying Hu,
  • Hao Wang,
  • Weiwei Gong,
  • Jieming Zhong,
  • Meng Wang,
  • Chunxiao Xu,
  • Keqing Gong,
  • Hao Xu,
  • Yuan Cao,
  • Kaixu Xie,
  • Lingli Chen,
  • Xiaomei Tu,
  • Chen Chen,
  • Xiaojun Li,
  • Li Yin,
  • Huilin Liu,
  • Yuan Liu,
  • Yi Liu,
  • Lei Yin,
  • Xian Xie,
  • Jing Wang,
  • Bo Xiao,
  • Pingsheng Lou,
  • Yuan Peng,
  • Libo Zhang,
  • Chan Qu,
  • Qili Jiang,
  • Yanling Chen,
  • Yan Zhao

摘要

Background

Mosaic chromosomal alterations (mCAs) served as a novel indicator of genomic aging. We aimed to investigate the association of expanded mCAs (cell fraction ≥ 10%) with all-cause and cause-specific mortality, and to examine the joint effect of expanded mCAs and frailty index (FI), an indicator of phenotypic aging, on mortality in two large prospective cohorts.

Methods

A total of 100,237 participants in the China Kadoorie Biobank (CKB) and 456,283 participants in the UK Biobank (UKB) were included, followed till Dec 31, 2023, and Nov 30, 2022, respectively. MoChA pipeline was used to detect expanded mCAs events and the subtypes. FIs were calculated using previously validated equations, with 28 items included in the CKB and 49 items in the UKB, and categorized participants into three groups: robust, prefrail, and frail. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to examine the associations of the expanded mCAs and joint categories of frailty-mCAs with all-cause and cause-specific mortality by using Cox proportional hazards models. The combined effect values of two cohorts were estimated using random-effects models by meta-analysis.

Results

The prevalence of expanded mCAs in the CKB and UKB was 2.2% and 3.4%, respectively. After a median follow-up of 17.2 years in the CKB and 13.7 years in the UKB, expanded mCAs carriers had a higher risk of all-cause (HRs [95% CIs]: 1.20 [1.16, 1.24]) and risks of cause-specific mortality (HRs [95% CIs]: 1.27 [1.21, 1.34], 1.13 [1.02, 1.25], and 1.24 [1.12, 1.37] for death from cancers, circulatory diseases, and respiratory diseases, respectively). Such associations largely did not overlap with FI, especially for all-cause and cancer mortality. Joint analyses revealed that individuals with lower frailty level but with expanded mCAs had a comparable and even higher risk of cancer mortality compared to those with higher frailty level but without mCAs. Similar pattern was also found in terms of adjusted 10-year cancer mortality rates.

Conclusions

Our findings suggested that expanded mCAs were significantly associated with all-cause and cause-specific deaths and could serve as a complement to the FI in providing a more comprehensive perspective on mortality risk, especially for cancer mortality.