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. 2025 Aug 7;16(1):1490.
doi: 10.1007/s12672-025-03370-w.

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

Xinqi Liu #  1 , Xu Xu #  2 , Peizhi Ye  1 , Zhenglong Jiang  1 , Le Tian  3 , Yukun Yin  4 , Li Feng  5
Affiliations

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

Xinqi Liu et al. Discov Oncol. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Breast cancer; Colocalization analysis; Inflammatory protein factors; Mendelian randomization.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study utilized publicly available summary-level GWAS data and did not require additional ethical approval. All original studies from which the data were derived (UK Biobank and FinnGen) obtained appropriate ethical approval from their respective institutional review boards and ethics committees. The UK Biobank study received ethical approval from the North West Multi-Centre Research Ethics Committee (REC reference: 11/NW/0382), and the FinnGen study was approved by the Finnish Institute for Health and Welfare (THL) and the Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS). No direct participant consent was required for this study as it exclusively used publicly available summary-level GWAS data. All participants in the original studies (UK Biobank and FinnGen) provided informed consent for participation in genetic research, including the use of their anonymized data in approved research projects. The current study did not involve direct contact with participants or access to individual-level data. Consent for publication: No specific consent to publish was required for this study as it utilized publicly available summary-level GWAS data that have been previously published and made available for research purposes. All original studies obtained appropriate consent from participants for the publication of research findings derived from their anonymized data. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic diagram illustrating the bidirectional two-sample MR and MVMR analyses investigating potential causal relationships between 91 inflammatory proteins and BC susceptibility. Arrows indicate hypothesized causal pathways based on genetic IVs. SNP, single nucleotide polymorphisms; IV, instrumental variable; MR, Mendelian randomization; UVMR, Univariable Mendelian Randomization; MVMR, Multivariable Mendelian randomization
Fig. 2
Fig. 2
Forest plot of inflammatory protein factors and BC risk(Bonferroni-adjusted p-values highlighted in red indicate significant associations at P < 0.0013). BC, breast cancer; SNP, single nucleotide polymorphisms; 95% CI, 95% confidence interval; IVW, inverse variance weighted; OR, odds ratio; LIFR, leukemia inhibitory factor receptor; CXCL5, C-X-C motif chemokine 5
Fig. 3
Fig. 3
Inverse MR of forest maps. MR, Mendelian randomization; BC, breast cancer; SNP, single nucleotide polymorphisms; 95% CI, 95% confidence interval; IVW, inverse variance weighted; b, beta; LIFR, leukemia inhibitory factor receptor; CXCL5, C-X-C motif chemokine 5
Fig. 4
Fig. 4
MVMR of forest maps. MVMR, Multivariable Mendelian randomization; BC, breast cancer; SNP, single nucleotide polymorphisms; 95% CI, 95% confidence interval; IVW, inverse variance weighted; LASSO, Least Absolute Shrinkage and Selection Operator; OR, odds ratio; LIFR, leukemia inhibitory factor receptor; CXCL5, C-X-C motif chemokine 5
Fig. 5
Fig. 5
Colocalization results. BC, breast cancer; LIFR, leukemia inhibitory factor receptor; CXCL5, C-X-C motif chemokine 5
See this image and copyright information in PMC

References

    1. Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet. 2021;397:1750–69. - PubMed
    1. Chen Z et al. Expressions of ZNF436, β-catenin, EGFR, and CMTM5 in breast cancer and their clinical significances. Eur J Histochem. 2021;65(1):3173. - PMC - PubMed
    1. Sun D, Luo X, Ma L, Wang Y, Zhang F. Identifying of miR-98-5p/IGF1 axis contributes breast cancer progression using comprehensive bioinformatic analyses methods and experiments validation. Life Sci. 2020;261:118435. - PubMed
    1. Taran FA, et al. Update breast cancer 2018 (Part 1) - Primary breast cancer and biomarkers. Geburtshilfe Frauenheilkd. 2018;78:237–45. - PMC - PubMed
    1. Dery KJ, et al. IRF-1 regulates alternative mRNA splicing of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in breast epithelial cells generating an immunoreceptor tyrosine-based Inhibition motif (ITIM) containing isoform. Mol Cancer. 2014;13:64. - PMC - PubMed

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