Exploring Bidirectional Causal Relationships between Antibody Responses to Infectious Agents and Breast Cancer through Mendelian Randomization and Meta-Analyses

Utilizing a GWAS dataset for 46 antibody-mediated immune responses (AMIRs) defined by 13 infectious pathogens and four distinct breast cancer (BrCa) datasets, we applied bidirectional Mendelian randomization (MR) analysis to assess their causalities, supplemented by meta-analysis to resolve inconsistency.Forward MR demonstrated that Anti-human herpes virus (HHV) 6 IgG seropositivity (IVW: OR=1.01; 95%CI, 1.00-1.02),HHV-6 IE1A antibody levels (IVW: OR=1.04; 95%CI, 1.02-1.06)and Helicobacter pylori (Hp) VacA antibody levels (IVW: OR=1.02; 95%CI, 1.00-1.04)were positively associated with BrCa risk.In reverse MR, BrCa was positively associated with Polyomavirus 2 JC VP1 (JCPyV) antibody levels (IVW: OR=1.07; 95%CI, 1.04-1.11),and negatively with Anti-Hp IgG seropositivity (IVW: OR=0.93; 95%CI, 0.88-0.97)and Anti-varicella zoster virus (VZV) IgG seropositivity (IVW: OR=0.84; 95%CI, 0.79-0.90).Summary-data-based MR (SMR) analyses were performed to identify potential mediators.Functional analysis revealed the genes mapped to BrCa were enriched in microbial infection and immune-related pathways.These findings suggest HHV-6 and Hp are risk factors for BrCa and BrCa may increase susceptibility to JCPyV infection, which highlights the importance of preventing breast cancer by addressing pathogenic infections early and maintaining healthy microbiota.