The effects of the interaction of genetic predisposition with lifestyle factors on bladder cancer risk

Objectives: To investigate the association of polygenic risk score (PRS) and bladder cancer (BC) risk and whether this PRS can be offset by a healthy lifestyle. Methods: Individuals with BC (n = 563) and non-BC controls (n = 483 957) were identified in the UK Biobank, and adjusted Cox regression models were used. A PRS was constructed based on 34 genetic variants associated with BC development, while a healthy lifestyle score (HLS) was constructed based on three lifestyle factors (i.e., smoking, physical activity, and diet). Results: Overall, a negative interaction was observed between the PRS and the HLS (P = 0.02). A 7% higher and 28% lower BC risk per 1-standard deviation (SD) increment in PRS and HLS were observed, respectively. A simultaneous increment of 1 SD in both HLS and PRS was associated with a 6% lower BC risk. In addition, individuals with a high genetic risk and an unfavourable lifestyle showed an increased BC risk compared to individuals with low genetic risk and a favourable lifestyle (hazard ratio 1.55, 95% confidence interval 1.16–1.91; P for trend <0.001). Furthermore, population-attributable fraction (PAF) analysis showed that 12%–15% of the BC cases might have been prevented if individuals had adhered to a healthy lifestyle. Conclusion: This large-scale cohort study shows that a genetic predisposition combined with unhealthy behaviours have a joint negative effect on the risk of developing BC. Behavioural lifestyle changes should be encouraged for people through comprehensive, multifactorial approaches, although high-risk individuals may be selected based on genetic risk.