Although air pollution is recognized as a contributor to accelerated biological aging, its associations with clinically significant liver-related outcomes and the potential role of proteomic aging remain unclear. We aimed to evaluate the associations of key air pollutants with liver-related outcomes and the potential mediating role of proteomic aging clocks. Among 504,006 China Kadoorie Biobank participants without liver disease or cancer, we used time-varying Cox regression to assess associations of PM2.5, PM10, NO2, and warm-season O3, and their mixtures with liver-related events (LRE) and liver-related mortality (LRM), and mediation analyses to examine the role of proteomic aging clocks (i.e., ProtAge). Long-term exposure to PM2.5, PM10, NO2, and warm-season O3 showed significant positive associations with LRE, while PM2.5, PM10, and NO2 were also positively associated with LRM. A 1-unit increment in the weighted pollutant score was associated with an 81% higher risk of LRE (hazard ratio [HR]=1.81 [1.65-1.98]) and a 17% higher risk of LRM (HR=1.17 [1.05-1.31]). Acceleration in ProtAge was associated with higher risks of LRE (HR=1.86 [1.16-2.97]) and LRM (HR=4.43 [3.02-6.50]). ProtAge accounted for an estimated 7.1% and 12.5% of the associations of pollutant mixtures with LRE and LRM, respectively. Among proteins in ProtAge, CD248, GDF15, TNFRSF6B, and XG showed concordant associations in pollutant mixture-protein and protein-LRE analyses. Long-term air pollution was associated with higher risks of clinically significant liver-related outcomes. These findings suggest a possible role of proteomic aging in the association between air pollution and liver-related outcomes, warranting further investigation.
BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a risk factor for cardiovascular disease (CVD). However, the risk of liver-related events (LREs) after CVD is often overlooked. We investigated the association between incident CVD and subsequent long-term LRE risk among individuals with MASLD.
METHODS
We used UK Biobank data to examine whether incident CVD (coronary heart disease [CHD], myocardial infarction [MI], heart failure [HF], or atrial fibrillation [AF]) was associated with subsequent long-term LREs (cirrhosis, decompensation, hepatocellular carcinoma, or liver-related death) in MASLD. Semi-Markov multi-state and time-dependent Cox regression models estimated transition rates and adjusted hazard ratios (aHRs). Imaging and proteomic data explored biological mechanisms.
RESULTS
Among 142,454 individuals with MASLD, 22,630 (15.9%) developed incident CVD, and 2635 (1.8%) developed subsequent LREs over a median of 15.1 years. The transition rate from CVD to LREs was higher than the direct progression from MASLD to LREs (3.56 vs. 1.08 per 1000 person-years). Time-dependent Cox regression showed that incident CVD was associated with a higher risk of subsequent LREs (aHR 1.93, 95%CI 1.73-2.14). The risk varied by CVD subtypes, with HF highest, followed by AF, CHD, and MI (all P < 0.001). Exploratory integrated multi-omics analyses revealed associations between cardiac dysfunction and hepatic parameters, and identified a shared proteomic signature enriched in immune and fibrotic pathways.
CONCLUSIONS
Individuals with MASLD who experience a CVD event have a higher subsequent risk of long-term LREs. These findings underscore the value of targeted liver monitoring for high-risk individuals after CVD and integrated heart-liver co-management.
Li-You Lian, Qin-Fen Chen, Tianyi Xia et al.· Metabolism: Clinical and Exp...· 0 citations