Abstract MP68: Mosaic Chromosomal Alterations, Frailty and Cardiovascular Disease Mortality: A Population-based Cohort Study Among Chinese Adults

Background: Mosaic chromosomal alterations (mCAs), representing a group of large-scale structural alterations detected in a fraction of peripheral leukocytes, serve as an indicator of genomic aging. We aim to investigate the association between expanded mCAs (cell fraction ≥10%) and cardiovascular disease (CVD) mortality, and examine whether combining mCAs with frailty index (FI), an indicator of phenotipic aging, contribute to the prediction of CVD mortality. Methods: A total of 100,297 genotyped participants aged 30-79 years from China Kadoorie Biobank were included, whose baseline information were collected from 2004-2008 and followed till Dec 31, 2023. MoChA pipeline was used to detect expanded mCAs events, including mCAs on autosomes, and the loss of X and Y chromosomes. FI was calculated using a previously validated equation using 28 health-related variables, which categorized participants into three groups: robust (FI≤0.1), prefrail (0.1<FI≤0.25), and frail (FI≥0.25). We used Cox proportional hazards models to estimate the associations of the expanded mCAs, FI, as well as joint categories of expanded mCAs and FI with CVD mortality. Results: After a median follow-up of 17.2 years (IQR: 15.7-18.2), 13,655 deaths from CVD diseases were recorded. Expanded mCAs were associated with an increased risk of CVD mortality independent of FI (hazard ratio [HR] and 95% confidence interval [CI]=1.24 [1.13, 1.36]), including deaths from ischaemic heart diseases (IHD, 1.24 [1.08, 1.42]), from strokes (1.20 [1.03, 1.39]) and from pulmonary heart diseases (PHD, 2.20 [1.03, 4.68]). Compared with robust participants without expanded mCAs, frail participants with expanded mCAs had around three-times increased risks of CVD mortality (2.98 [2.17, 4.07]), deaths from IHD (3.18 [2.03, 4.96]), and death from strokes (2.79 [1.64, 4.74]), and had sixteen-times increased risks of PHD mortality (16.51 [3.63, 75.01]). Conclusion: Combining expanded mCAs, a novel pre-symptomatic marker, with frailty index might increase the prediction of death from multiple CVD diseases.