Abstract
OBJECTIVE: We aimed to investigate the interrelationships among polygenic risk scores (PRS), healthy lifestyle factors (HLFs), and colorectal cancer (CRC) risk in individuals with prediabetes. To investigate whether adherence to HLFs influence CRC risk in those with elevated PRS within this specific population. METHODS: Data from 22,408 prediabetes participants without CRC at baseline were analyzed from the UK Biobank. HLFs were graded using healthy lifestyle scores (HLSs) and classified as favorable, intermediate, or unfavorable, while the PRS for CRC was categorized as high, medium, or low. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for CRC risk. RESULTS: High PRS (HR: 2.36; 95% CI: 1.86-3.00) and medium PRS (HR: 1.42; 95% CI: 1.09-1.83) prediabetes were associated with increased CRC risk compared to those with low PRS. HLFs were linked to lower CRC risk in a dose-response manner, with never smoking (HR: 0.69; 95% CI: 0.57-0.84) and maintaining a healthy BMI (HR: 0.64; 95% CI: 0.49-0.82) associated with reduced CRC risk. Adherence to favorable HLFs may reduce the CRC risk in those with medium (HR: 0.51; 95% CI: 0.27-0.95) and high PRS (HR: 0.62; 95% CI: 0.39-0.99) over 15 years of follow-up. In participants with high PRS and unfavorable HLFs, the excess risk due to the additive interaction between PRS and HLFs was 1.41% (p < 0.01), especially for women (1.07%). CONCLUSIONS: There is an additive interaction of PRS and HLFs on CRC risk in individuals with prediabetes. Adopting favorable HLFs should be integrated into the management of prediabetes individuals to reduce the risk of CRC.