Immunological mediators in the causal relationship between latent autoimmune diabetes in adults and breast cancer: A Mendelian randomization analysis

To investigate the link between Latent Autoimmune Diabetes in Adults (LADA) and breast cancer (BC) subtypes using Mendelian randomization (MR) and identify potential immunological mediators. We used MR with genetic variants as instruments, leveraging genome-wide association studies data from Europeans to assess the relationship between LADA and BC subtypes. The study evaluated the mediating role of immune cells and employed methods like inverse variance weighted, MR Egger, and MR-PRESSO to ensure robust results. LADA showed a negative association with overall BC, human epidermal growth factor receptor 2-positive BC, and estrogen receptor-positive BC. The FinnGen Biobank replication and meta-analysis confirmed these inverse relationships. CD11c on CD62L+ myeloid dendritic cells mediated the relationship between LADA and BC risk. Our study indicated a negative association between LADA and BC development, especially for human epidermal growth factor receptor 2-positive and estrogen receptor-positive subtypes, with CD11c on CD62L+ myeloid dendritic cells as a key mediator. These findings suggest potential mechanisms for LADA's influence on BC risk and highlight opportunities for targeted prevention and treatment.