Causal Relationship of Nitrogen Dioxides Air Pollution with Risk of Breast Cancer: A Two-sample Mendelian Randomization Study

Abstract Background Whether nitrogen dioxides (NO₂) air pollution genetically regulate the risk of breast cancer (BC) remains unknown. This study aims to investigate the cause-and-effect relationship of NO₂ air pollution with risk of BC.Methods A two-sample Mendelian randomization (MR) analysis was performed. The inverse-variance weighted (IVW) method and the weighted median (WM) method were applied to analyze the causal relationship. Cochran's Q statistic method and MR-Egger intercept test were used to assess heterogeneity and pleiotropy. MR-Egger regression and leave-one-out analysis were performed to assess sensitivity.Results IVW and WM methods demonstrated that NO₂ air pollution (with any potential confounders) was significantly associated with higher odds of BC overall [OR (95%CI): 1.69 (1.13, 2.54); 1.70 (1.02, 2.86)] (P = 0.01; 0.04). No significant heterogeneity (P = 0.33) and horizontal pleiotropy (P = 0.19) were present in the correlation analysis of NO₂ air pollution and risk of BC overall. After excluding SNPs of NO₂ with any potential confounders, IVW model demonstrated that NO₂ air pollution was still significantly associated with higher odds of BC overall [OR (95%CI): 4.15 (1.52, 11.31)] (P = 0.005). In the subtype analysis for ER + BC and ER- BC, causal relationship between NO₂ air pollution (removing any potential confounders) and estrogen receptor negative (ER-) BC was observed [OR (95%CI): 4.15 (1.52, 11.31)] (P = 0.005).Conclusion Increased exposure of NO₂ air pollution causally raises the chance of BC independent of ER, providing a recommendation to reduce NO₂ air pollution for future BC prevention.