烟草吸烟是膀胱癌最重要的危险因素。以往的研究已经确定了N-乙酰转移酶（NAT2）基因与膀胱癌风险的关联。NAT2基因编码一种酶，能够代谢芳香胺类致癌物，这些致癌物常见于烟草烟雾中。在我们的研究中，我们利用英国生物库（UK Biobank）的数据，这是一个大型前瞻性队列研究，评估了烟草吸烟与NAT2基因型和膀胱癌多基因风险评分（PRS）之间的潜在相互作用。我们采用Cox比例风险模型来评估相关性的强度。PRS是利用基因组关联研究鉴定出的膀胱癌遗传风险变异体所得。在欧洲人中，我们对390,678名符合条件的参与者进行了平均为10.1年的随访，并确定了769例膀胱癌发病案例。最高三等分位PR有烟者患膀胱癌的风险更高（HR：6.45，95％CI：4.51-9.24），相较于最低三等分位PR有烟者（HR：2.41，95％CI：1.52-3.84；P添加交互作用＝<.001）。类似的交互作用在基因预测的代谢NAT2表型和烟草吸烟之间也存在。具有较慢NAT2表型的现吸烟者患膀胱癌的风险增加（HR：5.70，95％CI：2.64-12.30），相对于具有较快NAT2表型的现吸烟者（HR：3.61，95％CI：1.14-11.37；P添加交互作用＝.100）。我们的研究支持在膀胱癌预防措施中考虑遗传和生活方式风险因素。© 2023 UICC.

Tobacco smoking is the most important risk factor for bladder cancer. Previous studies have identified the N-acetyltransferase (NAT2) gene in association with bladder cancer risk. The NAT2 gene encodes an enzyme that metabolizes aromatic amines, carcinogens commonly found in tobacco smoke. In our study, we evaluated potential interactions of tobacco smoking with NAT2 genotypes and polygenic risk score (PRS) for bladder cancer, using data from the UK Biobank, a large prospective cohort study. We used Cox proportional hazards models to measure the strength of the association. The PRS was derived using genetic risk variants identified by genome-wide association studies for bladder cancer. With an average of 10.1 years of follow-up of 390 678 eligible participants of European descent, 769 incident bladder cancer cases were identified. Current smokers with a PRS in the highest tertile had a higher risk of developing bladder cancer (HR: 6.45, 95% CI: 4.51-9.24) than current smokers with a PRS in the lowest tertile (HR: 2.41, 95% CI: 1.52-3.84; P for additive interaction = <.001). A similar interaction was found for genetically predicted metabolizing NAT2 phenotype and tobacco smoking where current smokers with the slow NAT2 phenotype had an increased risk of developing bladder cancer (HR: 5.70, 95% CI: 2.64-12.30) than current smokers with the fast NAT2 phenotype (HR: 3.61, 95% CI: 1.14-11.37; P for additive interaction = .100). Our study provides support for considering both genetic and lifestyle risk factors in developing prevention measures for bladder cancer.© 2023 UICC.