Department of Radiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
Laboratory of Medical Molecular Imaging, The First Affiliated Hospital of Shantou University Medical College, Shantou, China.
Front Immunol. 2024 Sep 26;15:1410994. doi: 10.3389/fimmu.2024.1410994. eCollection 2024.
Breast cancer (BC) remains a significant contributor to female mortality globally, with inflammation and the immune system implicated in its pathogenesis. To elucidate potential causal relationships, we evaluated the relationship among 731 immune cell phenotypes and BC be at risk by using Mendelian randomization (MR), while also exploring inflammatory proteins as mediators in this association.
We obtained immune cell genome-wide association study (GWAS) summary data and 91 inflammatory factors from the GWAS Catalog. BC GWAS data was obtained from the IEU Open GWAS project (ukb-b-16890 for discovery and GCST004988 for validation). We investigated the causal link between immune cells and BC risk by employing a two-sample MR method. Furthermore, we use a two-step MR to quantify the percentage of mediation of immune cell-BC causal effects mediated by inflammatory proteins. To make sure the causal findings were robust, a sensitivity analysis was done.
In both discovery and validation GWAS, a critical inverse correlation between CD4+ T cells and BC risk was found using MR analysis (Discovery: OR, 0.996; P = 0.030. Validation: OR, 0.843; P = 4.09E-07) with Caspase 8 levels mediating 18.9% of the reduced BC risk associated with immune cells(Mediation proportion=a×b/c, Discovery:0.151×-0.005/-0.004 = 18.9%; Validation:0.151×-0.214/-0.171 = 18.9%).
Our study establishes a causal connection linking CD4+ T cells and BC, with Caspase 8 levels partially mediating this relationship. These findings enhance our genetic and molecular comprehension of BC, suggesting potential pathways for future BC immunotherapy drug development.
乳腺癌（BC）仍然是全球女性死亡的主要原因，炎症和免疫系统与该病的发病机制有关。为了阐明潜在的因果关系，我们使用孟德尔随机化（MR）评估了 731 种免疫细胞表型与 BC 风险之间的关系，同时还探讨了炎症蛋白在这种关联中的中介作用。
我们从 GWAS 目录中获得了免疫细胞全基因组关联研究（GWAS）汇总数据和 91 种炎症因子。BC GWAS 数据来自 IEU Open GWAS 项目（用于发现的 ukb-b-16890 和用于验证的 GCST004988）。我们通过两样本 MR 方法研究了免疫细胞与 BC 风险之间的因果关系。此外，我们使用两步 MR 来量化炎症蛋白介导的免疫细胞-BC 因果效应的比例。为了确保因果发现的稳健性，我们进行了敏感性分析。
在发现和验证 GWAS 中，使用 MR 分析发现 CD4+T 细胞与 BC 风险之间存在显著的负相关（发现：OR，0.996；P=0.030. 验证：OR，0.843；P=4.09E-07），Caspase 8 水平介导了免疫细胞与 BC 风险降低相关的 18.9%（中介比例=a×b/c，发现：0.151×-0.005/-0.004=18.9%；验证：0.151×-0.214/-0.171=18.9%）。
我们的研究建立了 CD4+T 细胞与 BC 之间的因果关系，Caspase 8 水平部分介导了这种关系。这些发现增强了我们对 BC 的遗传和分子理解，为未来的 BC 免疫治疗药物开发提供了潜在的途径。
