Song Mingyu, Shao Zilun, Han Yuting, Zhao Yuxuan, Lv Jun, Yu Canqing, Pei Pei, Yang Ling, Millwood Iona Y, Walters Robin G, Chen Yiping, Du Huaidong, Yang Xiaoming, Wang Mengwei, Chen Junshi, Chen Zhengming, Genovese Giulio, Terao Chikashi, Li Liming, Sun Dianjianyi
Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China.
Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, 100191, China.
BMC Med. 2025 Nov 11;23(1):629. doi: 10.1186/s12916-025-04452-w.
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.
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.
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.
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.
嵌合染色体改变（mCAs）是基因组衰老的一种新指标。我们旨在研究扩展型mCAs（细胞比例≥10%）与全因死亡率和特定病因死亡率之间的关联，并在两个大型前瞻性队列中检验扩展型mCAs与衰弱指数（FI，一种表型衰老指标）对死亡率的联合影响。
纳入了中国嘉道理生物银行（CKB）的100237名参与者和英国生物银行（UKB）的456283名参与者，分别随访至2023年12月31日和2022年11月30日。使用MoChA流程检测扩展型mCAs事件及其亚型。使用先前验证的方程计算FI，CKB中包含28项，UKB中包含49项，并将参与者分为三组：强健、脆弱前期和脆弱。通过Cox比例风险模型估计调整后的风险比（HRs）和95%置信区间（CIs），以检验扩展型mCAs以及衰弱 - mCAs联合类别与全因死亡率和特定病因死亡率之间的关联。通过荟萃分析使用随机效应模型估计两个队列合并后的效应值。
CKB和UKB中扩展型mCAs的患病率分别为2.2%和3.4%。在CKB中进行了17.2年的中位随访，在UKB中进行了13.7年的中位随访后，扩展型mCAs携带者的全因死亡风险更高（HRs [95% CIs]：1.20 [1.16, 1.24]），特定病因死亡风险也更高（HRs [95% CIs]：因癌症、循环系统疾病和呼吸系统疾病死亡的风险分别为1.27 [1.21, 1.34]、1.13 [1.02, 1.25]和1.24 [1.12, 1.37]）。这些关联在很大程度上与FI不重叠，尤其是在全因死亡率和癌症死亡率方面。联合分析显示，与衰弱程度较高但无mCAs的个体相比，衰弱程度较低但有扩展型mCAs的个体患癌症死亡的风险相当甚至更高。在调整后的10年癌症死亡率方面也发现了类似模式。
我们的研究结果表明，扩展型mCAs与全因死亡和特定病因死亡显著相关，并且在提供更全面的死亡风险视角方面，尤其是对于癌症死亡率，可作为FI的补充。
