BACKGROUND AND OBJECTIVE: We determined the impact of genetic susceptibility and its interaction with smoking and air pollution on the risk of developing lung adenocarcinoma. METHODS: This retrospective case-control study utilised data from Taiwan Precision Medicine Initiative (TPMI) project conducted between June 2019 and November 2022. The study population consisted of lung adenocarcinoma patients and 1:4 age-, gender-, and index year-matched non-lung cancer controls. We analysed polygenic risk scores (PRS), smoking status, as well as PM RESULTS: A total of 681 lung adenocarcinoma patients and 2724 non-lung cancer participants were included. PRS was significantly higher among lung adenocarcinoma patients than controls (p <
0.001). Overall, a higher PRS was associated with a higher risk of lung adenocarcinoma. A high PM CONCLUSION: PRS significantly predicted lung adenocarcinoma incident cases in a dose-dependent manner among never-smokers. The PRS effect was not noted in smokers. The results were consistent among participants exposed to different air pollution levels.