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Background <p>Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition with increasing evidence of comorbidity with breast cancer (BRCA). While epidemiological studies suggest an association, the underlying genetic mechanisms remain largely unexplored.</p> Methods <p>We conducted a comprehensive genome-wide investigation to explore the shared genetic basis between IBD (including CD and UC) and breast cancer. Summary statistics from large-scale GWAS were analyzed using linkage disequilibrium score regression (LDSC), GNOVA, stratified LDSC (S-LDSC), MAGMA, PLACO, and summary-data-based Mendelian randomization (SMR). Tissue-specific enrichment was evaluated using GTEx data, and functional annotation was performed using FUMA.</p> Results <p>We identified significant genetic correlations between IBD and breast cancer at the genome-wide level. Subsequent pleiotropy analyses detected 83 genome-wide significant pleiotropic SNPs and 24 shared risk loci, including 9p24.1 and 10q21.2, involving key immune-regulatory genes such as <i>JAK2</i>, <i>CD274</i>, and <i>ZNF365</i>. MAGMA and FUMA revealed enrichment of shared genes in immune pathways such as cytokine signaling, JAK–STAT signaling, and antigen presentation. Tissue-specific analyses indicated significant expression of pleiotropic genes in the colon, terminal ileum, and breast. SMR analysis further supported the transcriptional regulatory role of genes like <i>P4HA2</i>, <i>ZNF365</i>, <i>SLC22A4</i>, and <i>SLC22A5</i> in both diseases.</p> Conclusion <p>This study presents the first systematic genetic evidence of a shared immunogenetic basis between IBD and breast cancer. The identification of pleiotropic loci and candidate drug targets provides novel insights into inflammation-associated tumorigenesis and lays the groundwork for future cross-disease prevention and therapeutic strategies.</p>

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Genetic and immune regulatory links between inflammatory bowel disease and breast cancer involving the JAK STAT PD L1 axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Ling Zeng,
  • Jingzhi Zhang,
  • Xue Liu,
  • Xueping Yang,
  • Qihong Nie

摘要

Background

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition with increasing evidence of comorbidity with breast cancer (BRCA). While epidemiological studies suggest an association, the underlying genetic mechanisms remain largely unexplored.

Methods

We conducted a comprehensive genome-wide investigation to explore the shared genetic basis between IBD (including CD and UC) and breast cancer. Summary statistics from large-scale GWAS were analyzed using linkage disequilibrium score regression (LDSC), GNOVA, stratified LDSC (S-LDSC), MAGMA, PLACO, and summary-data-based Mendelian randomization (SMR). Tissue-specific enrichment was evaluated using GTEx data, and functional annotation was performed using FUMA.

Results

We identified significant genetic correlations between IBD and breast cancer at the genome-wide level. Subsequent pleiotropy analyses detected 83 genome-wide significant pleiotropic SNPs and 24 shared risk loci, including 9p24.1 and 10q21.2, involving key immune-regulatory genes such as JAK2, CD274, and ZNF365. MAGMA and FUMA revealed enrichment of shared genes in immune pathways such as cytokine signaling, JAK–STAT signaling, and antigen presentation. Tissue-specific analyses indicated significant expression of pleiotropic genes in the colon, terminal ileum, and breast. SMR analysis further supported the transcriptional regulatory role of genes like P4HA2, ZNF365, SLC22A4, and SLC22A5 in both diseases.

Conclusion

This study presents the first systematic genetic evidence of a shared immunogenetic basis between IBD and breast cancer. The identification of pleiotropic loci and candidate drug targets provides novel insights into inflammation-associated tumorigenesis and lays the groundwork for future cross-disease prevention and therapeutic strategies.