Combined association of genetic predisposition and healthy lifestyle with lung cancer risk: a population-based cohort study

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Background: Polygenic susceptibility and modifiable lifestyle behaviors contribute to lung cancer, but their interaction and combined impact on lung cancer hazard and potential biological correlations remain incompletely characterised. This study aimed to evaluate the independent and combined associations of polygenic risk and healthy lifestyle with lung cancer hazard and to explore potential biological correlations underlying these associations. Methods: We analyzed data of 254,874 UK Biobank (UKB) participants. A five-component lifestyle score (smoking, alcohol intake, diet, physical activity and sedentary behavior) was summed [0-5] and categorized as unfavorable (0-1 factors), intermediate [2] and favorable [3-5]. An 18-single nucleotide polymorphism (SNP) polygenic risk score (PRS) was standardized and categorized into tertiles (low/intermediate/high). Cox proportional hazards models estimated associations with lung cancer hazard; additive interaction was assessed using the relative excess risk due to interaction (RERI). Mediation analyses of peripheral markers and circulating proteins were exploratory. Results: Among 254,874 UKB participants, 2,021 lung cancers occurred over a median of 11.69 years. A favorable lifestyle was associated with lower lung cancer hazard [hazard ratio (HR) 0.34; 95% confidence interval (CI): 0.30-0.38; P<0.001], while high PRS was associated with higher hazard (HR 1.62, 95% CI: 1.45-1.81; P<0.001). In the high PRS group, favorable lifestyle remained protective (HR 0.36, 95% CI: 0.30-0.44; P<0.001), whereas intermediate lifestyle was not statistically significant (HR 0.85, 95% CI: 0.68-1.05; P=0.13). The global multiplicative interaction between lifestyle class and PRS category was not significant (P for global interaction =0.49), although selected additive interaction signals were observed, including high PRS combined with intermediate lifestyle (RERI 0.92, 95% CI: 0.31-1.55). Exploratory mediation suggested partial signals for inflammatory markers and proteins (WFDC2, PIGR, PRSS8). Conclusions: This large-scale prospective study confirms the protective association of a healthy lifestyle with a lower lung cancer hazard. Importantly, in individuals with high genetic susceptibility, moderate lifestyle improvements may not fully offset the elevated hazard, underscoring the need for more comprehensive lifestyle interventions in this high genetic-susceptibility population. Mediation findings provide hypothesis-generating clues for future mechanistic work.

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