Smoking metabolic signature modifies the risk of colorectal cancer and interacts with genetic susceptibility: a large-scale prospective cohort study

Smoking tobacco is proven to be associated with higher colorectal cancer (CRC) risk. However, the metabolic pathways of smoking and how they relate to CRC risk are unclear. A total of 227,898 participants from the UK Biobank were included. A two-stage strategy with a combination of linear regression and Mendelian randomization analysis was employed to identify smoking-related metabolites. Then the elastic net (EN) regression model was used to construct smoking-related metabolic signature. Multivariable Cox regression, Mediation analysis, and interaction analysis were employed to illustrate the associations of smoking and smoking related metabolic signature on the risk of CRC. Furthermore, the interaction between genetic susceptibility and smoking metabolic signature was estimated based on relative excess risk due to interaction (RERI) and multiplicative-scale interaction. During a follow-up of 12.5 years, 3,328 incident CRC patients were observed. We identified 71 smoking-related metabolites and screened 42 of them metabolites by EN model to construct smoking-related metabolic signature. We observed smoking and smoking metabolic signature were both associated with the elevated risk of CRC, with a hazard ratio (HR) value of 1.27 and 1.38, respectively. Mediation analysis revealed metabolic signature can mediate 10.03% in the association between smoking and CRC risk. The additive interaction between genetic susceptibility and metabolic signature was statistically significant (RERI = 0.70, 95% confidence interval CI = 0.29–1.10). The detrimental impact of smoking on CRC risk is mediated partially by smoking metabolic signature, which is synergistic with genetic susceptibility.