Exploring the Causal Effects of 731 Immune Cell Phenotypes on Asthma: A Bidirectional Two-Sample Mendelian Randomization Study

Background: Asthma is a common chronic respiratory condition characterized by reversible airflow obstruction, bronchial hyperresponsiveness, and inflammation, influenced by genetic predispositions, environmental exposures, and immune responses. Current treatments focus primarily on symptom management, underscoring the need for a deeper understanding of the disease mechanisms. Methods: This study employed Mendelian randomization (MR) to investigate the causal relationships between 731 immune cell phenotypes and asthma susceptibility. Using genetic variants as instrumental variables, we aimed to address confounding and reverse causation biases typical of observational studies. Data were sourced from the FinnGen database's GWAS summary statistics and immune trait data from the GWAS catalog. Various MR methods, including MR Egger, Weighted Median, Inverse Variance Weighted, Simple Mode, and Weighted Mode, were utilized. Results: Our study has identified six immune cell phenotypes that exhibit potential causal relationships with asthma.After adjustments for a False Discovery Rate (FDR) less than 0.05, the expression of HLA-DR on plasmacytoid dendritic cells (DCs) was significantly associated with asthma, with an odds ratio (OR) of 1.054 and a 95% confidence interval (CI) ranging from 1.029 to 1.080 (P = 2.02E-05, PFDR = 0.015).The following immune phenotypes also demonstrated notable associations:CD62L− CD86+ myeloid DC percentage (p = 3.354E-04; PFDR = 0.078; 95% CI = 1.031 to 1.049),CD3 expression on CD4+ regulatory T cells (Tregs) (p = 1.661E-04; PFDR = 0.061; 95% CI = 0.959 to 0.980),CD33 expression on dimly expressed CD33 HLA-DR+ CD11b− cells (p = 5.471E-04; PFDR = 0.078; 95% CI = 1.019 to 1.030),CD33 on monocytic myeloid-derived suppressor cells (Mo MDSCs) (p = 6.0433E-04; PFDR = 0.078; 95% CI = 1.018 to 1.028),HLA-DR expression on CD33− HLA-DR+ cells (p = 4.472E-04; PFDR = 0.078; 95% CI = 1.064 to 1.102). Similarly, we conducted reverse MR analysis, which revealed no significant association between immune traits and asthma at a significance level of 0.05. Conclusions: Our findings emphasize the significant role of specific immune cell phenotypes in asthma pathogenesis and suggest potential targets for precision medicine strategies.