Multiple Group Mendelian Randomization Analysis Reveals the Potential Mechanisms of Immune-Related Gene Expression and DNA Methylation in Airway Allergic Diseases

目的：识别免疫相关基因在气道过敏性疾病(Airway allergic disease, AAD)中的因果效应和潜在机制。方法：从ImmPort数据库提取免疫相关基因。使用基于汇总数据的孟德尔随机化(Summary data-based Mendelian randomization, SMR)对过敏性鼻炎(Allergic rhinitis, AR)和过敏性哮喘(Allergic asthma, AA)的全基因组关联研究(genome-wide association study, GWAS)数据与血液中的表达数量性状位点(expression quantitative trait loci, eQTL)和甲基化数量性状基因位点(methylation quantitative trait loci, mQTL)进行整合分析，同时结合共定位分析共同确定免疫相关基因在气道过敏性疾病风险中潜在的调控机制。结果：通过整合SMR分析和共定位分析结果，确定TNFRSF1B表达[OR = 1.481, 95% CI (1.235~1.775), PFDR = 0.004]和甲基化位点cg13471521 [OR = 0.765, 95% CI (0.661~0.884), PFDR = 0.033]与AR发病相关；CD247 [OR = 0.813, 95% CI (0.721~0.915), PFDR = 0.024]、FCER1G [ OR = 1.068, 95% CI (1.029~1.109), PFDR = 0.213]和PSMD5 [OR = 1.259, 95% CI (1.101~1.439), PFDR = 0.026]与AA风险相关，以及它们的甲基化位点cg01833122、cg10375409、cg09070378、cg09833538和cg14255062与AA发病相关。结论：这项研究通过孟德尔随机化和共定位分析阐明了免疫相关基因表达和DNA甲基化在气道过敏性疾病发病中的作用，为临床实践提供了新的方向。Objective: To identify the causal effects and potential mechanisms of immune-related genes in airway allergic disease (AAD). Method: Immune-related genes were extracted from the ImmPort database. Summary data-based Mendelian randomization (SMR) was used to integrate genome-wide association study (GWAS) data for allergic rhinitis (AR) and allergic asthma (AA) with expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) in blood, and combined colocalization analysis was performed to jointly determine the potential regulatory mechanisms of immune-related genes in the risk of airway allergic diseases. Results: By integrating SMR analysis and colocalization analysis results, we identified that TNFRSF1B expression [OR = 1.481, 95% CI (1.235~1.775), PFDR = 0.004] and methylation site cg13471521 [OR = 0.765, 95% CI (0.661~0.884), PFDR = 0.033] were associated with the onset of AR; CD247 [OR = 0.813, 95% CI (0.721~0.915), PFDR = 0.024], FCER1G [OR = 1.068, 95% CI (1.029~1.109), PFDR = 0.213], and PSMD5 [OR = 1.259, 95% CI (1.101~1.439), PFDR = 0.026] were associated with the risk of AA, as well as their methylation sites cg01833122, cg10375409, cg09070378, cg09833538, and cg14255062 were associated with the onset of AA. Conclusion: This study elucidates the role of immune-related gene expression and DNA methylation in the pathogenesis of airway allergic diseases through Mendelian randomization and colocalization analysis, providing new directions for clinical practice.