探索多发性骨髓瘤的病理生物学和免疫细胞特征：来自双向基因分析的证据。
Exploring multiple myeloma pathobiology and immune cell signatures: Evidence from bidirectional genetic analysis.
作者信息
Tian Ying, Chen Wenming, Zhang Yue
机构信息
Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Department of Geriatrics, Beijing Haidian Hospital, Beijing, China.
出版信息
Medicine (Baltimore). 2025 Sep 5;104(36):e44276. doi: 10.1097/MD.0000000000044276.
The causal relationship between immune cell signatures and multiple myeloma (MM) pathobiology remains incompletely understood. This study aimed to explore the bidirectional causal associations between 731 circulating immune cell traits and MM risk using a two-sample, bidirectional Mendelian randomization (MR) approach. Two-sample MR analyses were conducted utilizing genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and MM GWAS datasets. Sensitivity analyses were performed to assess the robustness and reliability of the findings. Furthermore, meta-analyses were conducted on specific immune cell traits identified through the primary MR analyses to reinforce causal inferences. We identified 11 immune cell traits across 3 immune profiles - absolute cell count (AC), relative cell (RC) frequency, and median fluorescence intensity (MFI) - that exhibited significant causal associations with MM. Three immune traits were associated with an increased risk of MM: CD39+ CD8br %CD8br (P < .001), CD20 on CD20- CD38- cells (P = .002), and CD38 on transitional cells (P < .001). Conversely, 8 immune traits were found to confer a protective effect against MM, including CD11c+ monocyte AC (P = .002), Im myeloid-derived suppressor cell (MDSC) %CD33dim HLA-DR- CD66b- (P = .002), CD8dim %T cell (P < .001), CD8dim %leukocyte (P < .001), CD24 on CD24+ CD27+ cells (P = .003), CD4 on naive CD4+ cells (P < .001), CD11b on Mo MDSCs (P = .002), and HLA-DR on CD33dim HLA-DR+ CD11b- cells (P < .001). The reverse MR analysis demonstrated a significant causal association between the expression of CD19 on CD24+ CD27+ B cells and CD16 on CD14+ CD16+ monocytes in MM. These findings were validated through sensitivity tests and meta-analyses, which confirmed the robustness of the results and the absence of significant heterogeneity. Our bidirectional MR analyses provide compelling evidence for causal relationships between specific immune cell phenotypes and MM risk. These insights deepen the understanding of immune system dysregulation in MM pathogenesis and highlight potential immune-related targets for future therapeutic interventions.
免疫细胞特征与多发性骨髓瘤（MM）病理生物学之间的因果关系仍未完全明确。本研究旨在采用双样本双向孟德尔随机化（MR）方法，探究731种循环免疫细胞特征与MM风险之间的双向因果关联。利用731种免疫细胞表型的全基因组关联研究（GWAS）汇总统计数据和MM的GWAS数据集进行双样本MR分析。进行敏感性分析以评估研究结果的稳健性和可靠性。此外，对通过初步MR分析确定的特定免疫细胞特征进行荟萃分析，以加强因果推断。我们在3种免疫谱中确定了11种免疫细胞特征——绝对细胞计数（AC）、相对细胞（RC）频率和中位荧光强度（MFI）——它们与MM表现出显著的因果关联。三种免疫特征与MM风险增加相关：CD39⁺ CD8br %CD8br（P < 0.001）、CD20⁻ CD38⁻细胞上的CD20（P = 0.002）以及过渡细胞上的CD38（P < 0.001）。相反，发现8种免疫特征对MM具有保护作用，包括CD11c⁺单核细胞AC（P = 0.002）、免疫髓系来源抑制细胞（MDSC）%CD33dim HLA - DR⁻ CD66b⁻（P = 0.002）、CD8dim %T细胞（P < 0.001）、CD8dim %白细胞（P < 0.001）、CD24⁺ CD27⁺细胞上的CD24（P = 0.003）、幼稚CD4⁺细胞上的CD4（P < 0.001）、Mo MDSCs上的CD11b（P = 0.002）以及CD33dim HLA - DR⁺ CD11b⁻细胞上的HLA - DR（P < 0.001）。反向MR分析表明，MM中CD24⁺ CD27⁺ B细胞上CD19的表达与CD14⁺ CD16⁺单核细胞上CD16的表达之间存在显著的因果关联。这些发现通过敏感性测试和荟萃分析得到验证，证实了结果的稳健性且不存在显著异质性。我们的双向MR分析为特定免疫细胞表型与MM风险之间的因果关系提供了有力证据。这些见解加深了对MM发病机制中免疫系统失调的理解，并突出了未来治疗干预的潜在免疫相关靶点。
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