Association Between Allostatic Load, Genetic Susceptibility, and Liver Cancer Incidence: A Large‐Scale Prospective Cohort Study

Allostatic load (AL) reflects the cumulative physiological burden of chronic stress throughout life, potentially influencing cancer onset and prognosis. However, its association with primary liver cancer (PLC) risk and potential interaction with genetic susceptibility remains unclear. To investigate this, we analyzed 374,632 UK Biobank participants. AL was evaluated using a composite score of 13 cardiovascular, metabolic, and immune biomarkers, while a weighted polygenic risk score (PRS) categorized genetic susceptibility. Multivariable Cox proportional hazards models and restricted cubic splines were utilized to estimate hazard ratios (HRs) and evaluate dose-response relationships. Over a median 12.4-year follow-up, a significant dose-response correlation between AL and PLC risk was observed. In the fully adjusted model, a 1-unit increase in AL was associated with a 17% increased risk (HR = 1.17, 95% CI: 1.12-1.23), and participants in the highest AL quartile exhibited a 2.60-times higher risk than those in the lowest (HR = 2.60, 95% CI: 1.72-3.95). Despite no multiplicative interaction, stratified analyses revealed AL's impact was most substantial in individuals with intermediate genetic risk (HR = 2.00, 95% CI: 1.38-2.90), who constitute the population majority. Additionally, the risk was heightened in overweight/obese individuals and more pronounced among non-smokers. Ultimately, cumulative physiological stress, indicated by AL, is strongly associated with PLC, supporting the "wear-and-tear" theory of its development. This research highlights a "malleable zone" in individuals with moderate genetic risk, suggesting that lowering AL may meaningfully aid in preventing PLC.