Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Bidirectional causal associations between immune cell phenotypes and age-related macular degeneration subtypes: A mendelian randomization study.

Abstract

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the elderly population, characterized by two primary subtypes: dry AMD (dAMD) and wet AMD (wAMD). While immune mechanisms are implicated in AMD pathogenesis, the causal relationships between specific immune cell phenotypes and AMD subtypes remain incompletely characterized. METHODS: Bidirectional two-sample Mendelian randomization (MR) analysis was conducted to evaluate causal associations between 731 immune cell phenotypes and AMD subtypes. Immune cell phenotype data were sourced from publicly available GWAS datasets, encompassing 3757 individuals of European descent. AMD data were obtained from the Finnish Finngen R10 database, including 5239 wAMD cases and 6651 dAMD cases. The inverse-variance weighted (IVW) method was used as the primary analytical approach, complemented by reverse MR analysis to assess bidirectional relationships. RESULTS: The MR analysis identified significant causal associations between specific immune cell phenotypes and AMD subtypes. For wAMD, the expression of HLA-DR on CD14-CD16+ monocytes exhibited a positive association (OR = 1.11, P = 1.65 x 10-5), whereas CD25 on CD28+CD4+ T cells showed a negative association (OR = 0.87, P = 0.70 x 10-4). In the case of dAMD, the expression of HLA-DR on CD14+CD16+ monocytes was positively associated with disease risk (OR = 1.13, P = 0.84 x 10-6). Reverse MR analysis revealed that dAMD negatively influenced the expression levels of Effector Memory CD4-CD8- T cells (OR = 0.91, P = 0.36 x 10-4) and CD28+CD4-CD8- T cells (OR = 0.92, P = 0.90 x 10-4). Notably, no evidence supported a causal effect of wAMD on immune cell phenotypes. CONCLUSIONS: Using updated GWAS data, this study confirms subtype-specific immune associations in AMD and reports the first evidence of reverse causality: dAMD may directly modulates adaptive immune cell phenotypes. These findings refine our understanding of AMD immunopathogenesis and highlight potential targets for subtype-specific therapies.