Population attributable fraction of lung cancer due to genetic variants, modifiable risk factors, and their interactions: a nationwide prospective cohort study

Background: Genetic variants and modifiable risk factors (including environmental exposure and lifestyle) greatly contribute to the development of lung cancer. The population attributable fraction (PAF) of these risk factors, especially their interactive effects, has not been well quantified. Methods: A total of 398,577 participants were included in this analysis. There were 2504 incident lung cancer cases identified over an average 10.4-year follow-up. We applied Cox proportional hazards models to examine the associations between risk factors and incident lung cancer. We further developed a polygenic risk score and evaluated whether environmental factors modified the effect of genetic risk on incident lung cancer. Furthermore, we calculated the PAF for each risk factor, as well as their gene-environment additive interaction, and then combined them to create a weighted PAF that takes into consideration participants with overlapping risk factors. Results: Our analysis showed that smoking was the leading risk factor for lung cancer with a PAF of 63.73%. We observed additive interactions between smoking, PM2.5, NOx, and genetic risk, with PAFs of 17.85% (smoking high genetic risk interaction), 10.79% (smoking-intermediate genetic risk interaction), 5.30% (NOx-high genetic risk interaction), 6.55% (PM2.5-high genetic risk interaction), and 4.99% (PM2.5-intermediate genetic riskinteraction). We estimated that 73.46% of lung cancer cases could be attributable to potentially modifiable risk factors after adjusting for the correlation between them. Conclusion: High genetic risk and several modifiable factors may increase the risk of incident lung cancer. Participants with a high genetic risk may be more vulnerable to developing lung cancer if exposed to smoking and/ or high air pollution. Our findings provide evidence that the majority of incident lung cancer cases could be prevented by eliminating modifiable risk factors.