Causal Associations of Breast Cancer with 11 Immune Diseases: A Bidirectional Two-Sample Mendelian Randomization Study

Background: Some observational studies have suggested an association between breast cancer (BC) and the development of autoimmune and atopic diseases (AADs), but a causal link between them has not been established. Thus, a bidirectional two-sample Mendelian randomization (MR) method was employed to analyze the causality between BC and AADs. Methods: The study assessed causality between BC and eleven immune diseases by conducting a two-sample MR with publicly available summary statistics from genome-wide association studies in a European population. Single nucleotide polymorphisms linked with autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn's disease (CD), psoriasis vulgaris, systemic lupus erythematosus, primary biliary cholangitis and hypothyroidism and atopic diseases such as atopic dermatitis, allergic rhinitis, asthma and eczema were estimated in relative to BC by the inverse variance weighted method. And sensitivity analysis, MR-Egger intercept test, funnel plot and leave-one-out analysis, were all used to validate the consistency of the data. In addition, the bi-directional MR analysis was used in this study to investigate the direction of causality. Findings: After correcting for heterogeneity and accounting for horizontal multiplicity, the study results indicated a markedly higher incidence of BC among patients with a medical history of the following AADs: RA (odds ratio [OR]=1.04, 95% confidence interval [CI]: 1.01-1.08, P=0.02), UC (OR=1.04, 95% CI: 1.00-1.07, P=0.04) and CD (OR=1.04, 95% CI: 1.01-1.07, P=0.00). Bidirectional MR analysis indicated that BC has a causal effect on CD (OR=1.15, 95% CI: 1.04-1.26, P=0.00). Additionally, MR-Egger intercepts revealed no directional pleiotropic effects between them. Interpretation: The definite causal association of RA and UC with BC and the definite mutual effect of CD and BC suggest that these AADs may play an important role in the pathogenesis of BC.Funding: Grants of National Natural Science Foundation of China (NSFC) No. 81903350 to Xueqiong Zhou, No. 82130054 to Fei Zou, No. 32171408 to Chunqing Cai and No. 81602205 to Binxi Lei. The Guangdong Basic and Applied Basic Research Foundation No. 2021A1515010007 to Xueqiong Zhou. Guangzhou Science and Technology Project No. 202201011138 to Ying Wen, China Postdoctoral Science Foundation No. 2021M690783 to Ying Wen.Declaration of Interest: The authors have no conflict of interest.