Genetic determinants of inflammatory cytokines and their causal relationship with inflammatory disorders of breast: a two-sample Mendelian randomization study

This study utilized two-sample MR to investigate causality between genetically predicted inflammatory markers and the risk of IDB. This research leveraged publicly available GWAS summary statistics to collect data on inflammatory cytokines and IDB. The IVW method was primarily employed for causal inference, supplemented by weighted median, mode-based estimation, and MR-Egger regression. Stringent sensitivity methods included Cochran's Q test, MR-Egger regression, MR-PRESSO, and leave-one-out analyses to assess the robustness of the findings. This study selected 452 instrument variables (IVs) related to inflammatory factors. The IVW analysis revealed that GROa and RANTES/CCL5 exhibited causal relationships with IDB. Additionally, after removing outliers, significant causal associations were observed for IL-1ra and IL-9. Notably, the causal associations of RANTES/CCL5 and IL-9 with IBD remained significant after FDR correction. Upon integrating the findings from all sensitivity analyses, it is unlikely that heterogeneity and pleiotropy substantially influenced the observed relationships, underscoring the robustness of our findings. Our MR analysis identified the causal roles of specific inflammatory cytokines such as GROa, RANTES/CCL5, IL-1ra and IL-9 in the development of IDB. These findings deepen our understanding of the complex regulatory mechanisms involving inflammation in breast diseases and suggest directions for future research on biological pathways linking inflammation with IDB.