The Causal Role of Immune Cell Phenotypes and Inflammatory Factors in Childhood Asthma: Evidence From Mendelian Randomization

ABSTRACT Objective This study utilizes Mendelian randomization (MR) to explore the causal relationship between immune cell phenotypes, inflammatory factors, and childhood asthma, aiming to enhance our understanding and management of the disease. Methods A two‐sample MR approach was used to explore the causal relationships between 731 immune cell phenotypes, 91 inflammatory factors, and childhood asthma. The main analysis was performed using inverse variance weighting (IVW), with additional methods like weighted median, MR‐Egger, and weighted mode. Statistical significance was further assessed using false discovery rate (FDR) correction. Sensitivity analyses assessed heterogeneity (Cochran's Q test) and pleiotropy (MR‐Egger, MR‐PRESSO), while reverse causality was evaluated using the Steiger test. Findings were further validated through cohort studies and meta‐analyses to ensure robustness. Results Among 91 inflammatory factors, DNER, IL‐18 R1, and Osteoprotegerin increased childhood asthma risk, while CDCP1 and VEGF‐A were protective ( p < 0.05). Of 731 immune cell phenotypes, 45 showed significant links to asthma, with protective effects from CD45RA+ CD8+ T cells and HLA−DR+ NK cells, and increased risk from IgD‐CD38‐ B cells and CD8dim T cells ( p < 0.05). Specific SSC‐A parameters and higher MFI values for CD19, CD28, and CD3 were protective, while elevated MFI for CCR2 on monocytes and CD86 on myeloid dendritic cells increased risk. However, after further FDR correction, no statistically significant results were identified. Nonetheless, sensitivity and replication analyses, including meta‐analysis, confirmed the robustness of these associations. Conclusions This study provides a comprehensive investigation into the complex interplay between immune system dysregulation and childhood asthma. By identifying specific inflammatory factors and immune cell phenotypes linked to asthma risk and protection, the findings offer valuable insights into disease pathogenesis. While these results highlight potential targets for precision‐based therapeutic interventions, further research is needed to validate these associations and translate them into clinical applications.