Investigating the causal linkages between circulating inflammatory proteins and breast cancer risk and prognosis: Insights from a two-sample Mendelian randomization analysis

This Mendelian randomization (MR) study aims to explore the causal relationships between 91 circulating inflammatory proteins and the incidence and prognosis of breast cancer. Data on exposures were derived from previously published articles, and outcome-related data were obtained from genome-wide association studies databases. The main causal estimates were obtained using the inverse variance weighting (IVW) method. Cochran Q and Rücker Q heterogeneity tests were performed using both IVW and MR-Egger methods. The Egger-intercept method was utilized for pleiotropy testing, single nucleotide polymorphism exclusion tests were conducted for sensitivity analysis, and the F-statistic was calculated to assess the presence of weak instrument bias. Finally, the Mendelian Randomization Pleiotropy RESidual Sum and Outlier method was used to validate the causal associations between circulating inflammatory factors and the incidence and prognosis of breast cancer. A comprehensive analysis of 91 circulating inflammatory proteins revealed their causal associations with the incidence and prognosis of breast cancer. β-Nerve growth factor (NGF), cystatin-C-8, C-X-C motif chemokine (CXCL) 5, IL 15 receptor alpha subunit, IL 22 receptor alpha-1 subunit, matrix metalloproteinase 1 (MMP1), and tumor necrosis factor (TNF) ligand superfamily member 12 showed a causal relationship with the incidence of breast cancer. A positive correlation was observed between β-NGF levels and breast cancer incidence, with an odds ratio (OR) (95% confidence interval (CI)) (IVW method) of 1.1713 (1.0347-1.3259). A negative correlation was found between the levels of cystatin-C-8, CXCL 5, IL 15 receptor alpha subunit, IL 22 receptor alpha-1 subunit, MMP1, and TNF ligand superfamily member 12 and breast cancer incidence, with OR (95% CI) (IVW method) values of 0.8238 (0.7206-0.9416), 0.9117 (0.8471-0.9812), 0.9297 (0.8684-0.9953), 0.8030 (0.6957-0.9269), 0.8580 (0.7719-0.9537), and 0.9175 (0.8437-0.9977), respectively. Furthermore, negative causal associations were found between the levels of C-C motif chemokine 19, IL 18 receptor 1, and TNF-β (also known as lymphotoxin-α) and breast cancer survival, with OR (95% CI) (IVW method) values of 0.8644 (0.7563-0.9880), 0.8565 (0.7786-0.9422), and 0.8889 (0.7940-0.9951), respectively. No pleiotropy was detected in any of the study results. This study elucidates the positive and negative causal relationships between 91 circulating inflammatory proteins and the onset and prognosis of breast cancer.