免疫细胞表型在多发性骨髓瘤进展中的因果作用：全基因组关联研究的双向评估

Revealing the Causal Role of Immune Cell Phenotypes in the Progression of Multiple Myeloma: A Bidirectional Assessment Based on Genome-Wide Association Studies

摘要: 目的：既往的研究探讨了免疫细胞在多发性骨髓瘤中的作用，本研究进一步通过孟德尔随机化方法，评估731种免疫细胞表型与多发性骨髓瘤发病风险之间的因果关系，为阐明多发性骨髓瘤的发生机制和临床治疗提供遗传学依据。研究方法：本研究使用的731种免疫细胞表型与多发性骨髓瘤的数据分别来自相应的全基因组关联研究(GWAS)，采用逆方差加权(IVW)作为主要分析方法进行因果推断。并辅以MR-Egger、加权模式、简单模式和加权中位数以加强最终结果的稳健性。最后，通过敏感性分析验证了数据的稳定性和可行性，并通过反MR分析评估反向因果关系，以确定多发性骨髓瘤对免疫细胞表型的潜在影响。结果：IVW法的MR分析结果显示，7种免疫细胞表型与多发性骨髓瘤的发病风险呈正相关(P < 0.05, OR > 1)，4种免疫细胞表型与多发性骨髓瘤发病风险呈负相关(P < 0.05, OR > 1)，均未发现异质性或水平多效性(P > 0.05)。反向MR分析表明，多发性骨髓瘤与另外10种免疫细胞表型呈正相关(P < 0.05, OR > 1)，与16种免疫细胞表型呈负相关(P < 0.05, OR > 1)，同样未发现异质性和水平多效性(P > 0.05)。结论：通过全面的双向、双样本MR分析，本研究提供了遗传学证据支持多种免疫细胞表型与多发性骨髓瘤发病风险之间存在复杂因果关系，揭示了免疫系统与多发性骨髓瘤之间相互作用的复杂模式，为多发性骨髓瘤的免疫学基础提供了新见解，可能为未来针对免疫细胞的治疗策略提供方向。

Abstract: Purpose: Previous studies have explored the role of immune cells in multiple myeloma. This study further utilized the Mendelian randomization method to assess the causal relationship between 731 immune cell phenotypes and the risk of multiple myeloma onset, providing genetic evidence to elucidate the pathogenesis and clinical treatment of multiple myeloma. Research Methods: The 731 immune cell phenotypes used in this study and the data related to multiple myeloma were obtained from corresponding genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was adopted as the main analytical approach for causal inference. Additionally, MR-Egger, weighted mode, simple mode, and weighted median were used to enhance the robustness of the final results. Finally, through sensitivity analysis, the stability and feasibility of the data were verified, and reverse MR analysis was conducted to assess the reverse causal relationship to determine the potential impact of multiple myeloma on immune cell phenotypes. Results: The MR analysis results of the IVW method showed that 7 immune cell phenotypes were positively correlated with the risk of multiple myeloma (P < 0.05, OR > 1), and 4 immune cell phenotypes were negatively correlated with the risk of multiple myeloma (P < 0.05, OR > 1). No heterogeneity or level multiplicity was found (P > 0.05). The reverse MR analysis indicated that multiple myeloma was positively correlated with 10 other immune cell phenotypes (P < 0.05, OR > 1), and negatively correlated with 16 immune cell phenotypes (P < 0.05, OR > 1). Again, no heterogeneity or level multiplicity was found (P > 0.05). Conclusion: Through comprehensive bidirectional and two-sample MR analysis, this study provided genetic evidence supporting a complex causal relationship between multiple immune cell phenotypes and the risk of multiple myeloma. It revealed the complex interaction patterns between the immune system and multiple myeloma, offering new insights into the immunological basis of multiple myeloma and potentially providing directions for future immunological treatment strategies targeting immune cells.