Dissecting the role of inflammatory biomarkers in breast cancer: Insights from Mendelian randomization

Inflammatory biomarkers (including C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT], and serum amyloid A [SAA]) have been postulated to influence tumorigenesis, yet their causal relevance to breast cancer (BC) remains uncertain. We applied a two-sample Mendelian randomization (MR) framework to evaluate putative causal relationships between these circulating inflammatory factors and BC risk. Publicly available genome-wide association study summary statistics were used to identify, curate, and clump single-nucleotide polymorphisms that robustly trace CRP, IL-6, PCT, and SAA concentrations, which then served as instrumental variables. Causal estimates were generated with inverse-variance weighting, MR-Egger regression, weighted-median, simple-mode, and weighted-mode models. Heterogeneity was assessed by Cochran Q statistic, horizontal pleiotropy by the MR-Egger intercept, and robustness by leave-one-out as well as funnel-plot inspection. Two-sample MR demonstrated that genetically predicted SAA is positively associated with BC risk (inverse-variance weighting odds ratios = 1.002, 95% confidence interval 1.000-1.003, P = .023), whereas CRP, IL-6, and PCT exhibited no evidence of causal effects on BC in any MR model. Sensitivity analyses showed no substantial heterogeneity or directional pleiotropy, and causal estimates were stable after sequential SNP exclusion. In summary, the present MR study provides genetic evidence that elevated SAA causally increases the risk of developing BC, whereas CRP, IL-6, and PCT do not appear to exert independent causal influences.