Association of genetic risk and lifestyle with pancreatic cancer and their age dependency: a large prospective cohort study in the UK Biobank

Abstract Background Pancreatic cancer (PC) is influenced by both genetic and lifestyle factors. However, further research is still needed to comprehensively clarify the relationships among lifestyle, genetic factors, their combined effect on PC, and how these associations might be age-dependent. Methods We included 340,631 participants from the UK Biobank. Three polygenic risk score (PRS) models for PC were applied, which were derived from the previous study and were categorized as low, intermediate, and high. Two healthy lifestyle scores (HLSs) were constructed using 9 lifestyle factors based on the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) lifestyle score and the American Cancer Society (ACS) guidelines and were categorized as unfavorable, intermediate, and favorable. Data were analyzed using Cox proportional hazards models. Results There were 1,129 cases of incident PC during a median follow-up of 13.05 years. Higher PRS was significantly associated with an increased risk of PC (hazard ratio [HR], 1.58; 95% confidence intervals [CI], 1.47–1.71). Adhering to a favorable lifestyle was associated with a lower risk (HR, 0.48; 95% CI, 0.41–0.56). Participants with an unfavorable lifestyle and a high PRS had the highest risk of PC (HR, 2.84; 95% CI, 2.22–3.62). Additionally, when stratified by age, a favorable lifestyle was most pronounced associated with a lower risk of PC among participants aged ≤ 60 years (HR, 0.35; 95% CI, 0.23–0.54). However, the absolute risk reduction was more pronounced among those aged > 70 years (ARR, 0.19%, 95% CI, 0.13%–0.26%). A high PRS was more strongly associated with PC among participants aged ≤ 60 years (HR, 1.89; 95% CI, 1.30–2.73). Furthermore, we observed a significant multiplicative interaction and several significant additive interactions. Conclusions A healthy lifestyle was associated with a lower risk of PC, regardless of the participants' age, sex, or genetic risk. Importantly, our findings indicated the age-dependent association of lifestyle and genetic factors with PC, emphasizing the importance of early adoption for effective prevention and potentially providing invaluable guidance for setting the optimal age to start preventive measures.