Abstract
IgA nephropathy is the most common primary glomerular disease worldwide, with inflammation and autoimmune response mechanisms permeating the entire disease development process. The advancement of genome-wide association studies has enabled deeper understanding of the disease mechanisms and genetic susceptibility. Therefore, this study aims to explore the causal relationship between 731 immune cell types and the disease through Mendelian randomization (MR) analysis. This 2-sample MR study investigated bidirectional causal relationships using summary statistics for immune cells characteristics from the Genome-Wide Association Study (GWAS) catalog and IgA nephropathy from the FinnGen dataset. The study primarily utilized the Inverse Variance Weighted method for its main outcome. Additionally, the robustness of the results is further enhanced by analyses of heterogeneity, pleiotropy, and multiple sensitivity tests. After adjusting for false discovery rate (FDR), the study results revealed a bidirectional causal relationship between CD8 on terminally differentiated CD8+ T cells (OR = 0.77, 95% CI = 0.67-0.88, P = .0001) and CD4 on CD28+ CD4+ T cells (OR = 0.75, 95% CI = 0.64-0.87, P = .0001) with the risk of IgA nephropathy. CD64 on CD14+ CD16+ monocytes (OR = 0.66, 95% CI = 0.51-0.85, P = .0013) is considered a protective factor, while the percentages of CD8+ and CD8dim T cells (1.38, 95% CI = 1.17-1.63, P = .0002) in leukocytes are viewed as risk factors. This study employed genetic variation as an instrumental variable to explore the genetic association between immune cells and IgA nephropathy, aiming to offer new insights into early prevention and personalized treatment of the disease.