The Causal Relationship between Dermatomyositis and Lung Cancer Mediated by Immune Cells: A Mendelian Randomization Study with Mediation Analysis

目的：通过双向两样本MR方法探讨皮肌炎(Dermatomyositis, DM)、免疫细胞与肺癌(Lung cancer, LC)之间的因果关系，验证免疫细胞在其中起到的中介作用。方法：使用双向双样本孟德尔随机化(Mendelian Randomization, MR)法分析DM与LC及其各种亚型的因果关系，通过两步法MR探讨免疫细胞在DM与LC及各种亚型之间是否起到中介作用。使用MR-Egger截距法和MR-PRESSO法检查有无水平多效性，Cochran’s Q检查有无异质性。结果：根据MR分析结果，DM会增加患小细胞肺癌(Small cell lung cancer, SCLC)和肺腺癌(Lung adenocarcinoma, LUAD)的风险。38种免疫细胞表型与LC密切相关。其中，效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比，以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平，都参与介导了DM与LUAD以及小细胞肺癌SCLC之间的因果关系。结论：我们的研究结果表明，DM患者并发LUAD和SCLC发生风险将显著增加。此外，我们发现五种免疫细胞性状(效应记忆CD8+ T细胞在CD8+ T细胞中所占的百分比、静息CD4调节性T细胞上CD25的表达水平、IgD− CD38+ B细胞的绝对计数、效应记忆CD8+ T细胞在T细胞中所占的百分比，以及CD33+ HLA-DR+ CD14低表达细胞上CD45的表达水平)在DM患者并发LC中的发病过程中起到重要作用。针对这些免疫细胞性状的深入研究将进一步明确DM导致LC风险升高的病理生理机制。Objective: To explore the causal relationships among dermatomyositis (DM), immune cells, and lung cancer (LC) through the bidirectional two-sample Mendelian randomization (MR) method, and to verify the mediating role of immune cells in this process. Methods: The bidirectional two-sample Mendelian randomization (MR) method was used to analyze the causal relationships between DM and LC as well as its various subtypes. The two-step MR method was applied to explore whether immune cells played a mediating role between DM and LC and its various subtypes. The MR-Egger intercept method and the MR-PRESSO method were used to check for horizontal pleiotropy, and Cochran’s Q test was used to check for heterogeneity. Results: According to the results of the MR analysis, DM increases the risk of developing small cell lung cancer (SCLC) and lung adenocarcinoma (LUAD). 38 immune cell characteristics were closely related to LC. Among them, the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells all participated in mediating the causal relationships between DM and LUAD as well as SCLC. Conclusion: Our research results indicate that the risk of developing LUAD and SCLC in patients with DM will increase significantly. In addition, we found that five immune cell traits (the percentage of effector memory CD8+ T cells in CD8+ T cells, the expression level of CD25 on resting CD4 regulatory T cells, the absolute count of IgD− CD38+ B cells, the percentage of effector memory CD8+ T cells in T cells, and the expression level of CD45 on CD33+ HLA-DR+ CD14 low-expression cells) play an important role in the pathogenesis of LC in patients with DM. In-depth research on these immune cell traits will further clarify the pathophysiological mechanism by which DM leads to an increased risk of LC.