Genetic evidence for causal effects of inflammatory protein factors on breast cancer

Breast cancer (BC) represents a significant public health challenge characterized by complex pathogenic mechanisms. While inflammatory proteins are known to play crucial roles in cancer development, their causal relationships with breast cancer risk remain inadequately understood. This study employed Mendelian randomization (MR) analysis to investigate potential causal associations between inflammatory proteins and breast cancer susceptibility.

We utilized genome-wide association study (GWAS) data for inflammatory protein levels from 14,824 European individuals as exposure data. The primary outcome data were obtained from BC GWAS summary statistics, with an additional independent BC cohort serving as validation(FinnGen_R12). The primary analysis was conducted using inverse-variance weighted (IVW) method, supplemented by MR-Egger and weighted median approaches. Comprehensive sensitivity analyses included Cochran's Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. The causal direction was verified through Steiger test and reverse MR. We further performed multivariable MR (MVMR), linkage disequilibrium score regression (LDSC), and colocalization analysis to strengthen our findings.

After Bonferroni correction, we identified a significant inverse genetic association between Leukemia inhibitory factor receptor (LIFR) levels and BC risk. While C-X-C motif chemokine 5 (CXCL5) did not survive Bonferroni correction, it showed significant negative association with BC in MVMR analysis. Reverse MR analyses found no evidence of causal effects of BC on these inflammatory proteins, supporting the direction of our primary findings. Colocalization analysis revealed strong evidence of shared genetic variants between LIFR and BC, suggesting common genetic determinants underlying their relationship.

This study provides genetic evidence for causal relationships between inflammatory proteins and BC risk, particularly highlighting the protective role of LIFR. These findings enhance our understanding of BC pathogenesis and may inform future therapeutic strategies.