Abstract
PURPOSE: Glaucoma is characterized by progressive retinal ganglion cell loss and irreversible sight damage and is reported to be interacting with immunological dysregulation. Primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) are two of the most frequent subtypes. This study aimed to explore the associations between the immune system and glaucoma by investigating the causal relationships between POAG or PACG and immunocyte phenotypes. METHODS: A two-sample Mendelian randomization (MR) approach was carried out to comprehensively analyze the genetic variants associated 731 immunocyte phenotypes and their influence on glaucoma outcomes. Data were obtained from genome-wide association studies and the FinnGen consortium, with rigorous statistical methods applied to ensure the robustness of the study. RESULTS: Significant associations were identified between immunocyte phenotypes and glaucoma. Specifically, causal effects of 22 immunocyte phenotypes on POAG were observed, with CD25hi CD45RA- CD4 not regulatory T cell activated cells showing a bidirectional interaction. Additionally, 30 immunocyte phenotypes were found to have causal effects on PACG. Bidirectional interactions were identified with BAFF-R on immunoglobulin (Ig)D+ CD38- naive cells, BAFF-R on IgD+ CD38- unswitched memory cells, and CD62L on CD62L+ myeloid dendritic cells. CONCLUSIONS: The present results highlighted the essential role of immune regulation in the pathogenesis of glaucoma. These findings powerfully indicate the significance of exploring the therapeutic potentials of targeting different immune cells and immune responses to regulate both POAG and PACG. TRANSLATIONAL RELEVANCE: The present study highlighted immune-glaucoma interactions mediated by T-cell and monocyte phenotypes in primary open-angle glaucoma and primary angle-closure glaucoma development.