Air pollutants, genetic susceptibility, and bladder cancer risk: a prospective study

The contribution of long-term ambient air pollution to bladder cancer (BCa) risk remains unclear, and gene–environment interactions are underexplored. We investigated associations of major air pollutants with BCa, their interplay with genetic susceptibility, and the potentially avertable burden under intervention scenarios. We analyzed 469,105 BCa-free participants from the UK Biobank. Annual exposures to fine particulate matter < 2.5 μm (PM₂.₅), particulate matter < 10 μm (PM₁₀), nitrogen dioxide (NO₂), and nitrogen oxides (NOx) were estimated using 1 km × 1 km spatiotemporal models with complete residential histories to derive time-weighted cumulative exposures. Time-dependent Cox models estimated hazard ratios (HRs), adjusting for demographic, socioeconomic, and lifestyle factors. Polygenic risk scores were constructed to assess genetic susceptibility, and joint effects, interaction indices, population attributable fractions (PAFs), and intervention scenarios were examined. During a median follow-up of 15.4 years, 3,204 BCa cases were identified. All pollutants showed strong dose–response associations ( P < 0.05). Long-term exposure to PM₂.₅ (HR, 2.020; 95% CI, 1.919–2.127), PM₁₀ (HR, 1.657; 95%CI, 1.580–1.738), NOx (HR, 1.450; 95%CI, 1.391–1.513), and NO₂ (HR, 1.508; 95%CI, 1.441–1.578) were significantly associated with increased BCa risk. The elevated risk associated with air pollution was evident across all PRS strata. In joint analyses, participants with high genetic risk and high exposure had the greatest risks, with HRs up to 8.75 for PM₂.₅, 6.32 for PM₁₀, 4.79 for NOx, and 4.97 for NO₂. Additive interaction analyses revealed strong synergy, particularly for PM₂.₅ in high-risk individuals ( P < 0.001). The population attributable risk because of annual average PM₂.₅ concentration ≥Q4 level was 36.8%, followed by PM₁₀ (28.2%), NOx (24.8%), and NO₂ (24.7%). Achieving World Health Organization (WHO) guideline levels was projected to theoretically avert up to 80% of PM₂.₅-related cases. Ambient air pollution is strongly assossciated with BCa risk, particularly among genetically susceptible individuals, and may represent a potential target for future prevention. Stricter air quality standards could potentially mitigate BCa burden.