Abstract
BACKGROUND: Exposure to air pollutants is a significant global health concern linked to numerous diseases. However, the causal role of air pollution in the development of head and neck cancer (HNC) remains uncertain. METHODS: To investigate this relationship, we employed two-sample Mendelian randomization (TSMR), MRlap, and multivariable Mendelian randomization (MVMR) analyses using publicly available genome-wide association study (GWAS) datasets. Additionally, we explored potential mediating proteins and underlying biological mechanisms. RESULTS: Our findings revealed a significant causal association between nitrogen dioxide (NO₂) exposure and increased risk of HNC (odds ratio [OR] = 1.008, 95% confidence interval [CI]: 1.001-1.016, P = 0.036), as well as between nitrogen oxides (NOₓ) and HNC (OR = 1.010, 95% CI: 1.003-1.018, P = 0.005). Specifically, NOₓ exposure was causally linked to oral and oropharyngeal cancers (OR = 1.009, 95% CI: 1.003-1.016, P = 0.007). These associations were supported by sensitivity analyses, pleiotropy assessments, MRlap, and MVMR approaches. Furthermore, sushi domain-containing protein 2 (SUSD2) and bactericidal permeability-increasing protein (BPI) were identified as potential mediators, and protein methylation was identified as a plausible underlying mechanism linking air pollutant exposure with HNC. CONCLUSION: Exposure to NO₂ and NO(x) air pollutants is causally associated with an elevated risk of developing HNC. Reducing exposure to these pollutants may be an effective strategy for decreasing the incidence of HNC.