<b>Evaluating the link between immune characteristics and IgA nephropathy via a bidirectional mendelian randomization study</b>

<b>Background </b>Immunoglobulin A nephropathy (IgAN), a predominant primary glomerulonephritis worldwide, contributes substantially to end-stage renal disease. Currently, there is no specific therapy for IgAN, primarily due to incomplete understanding of its pathogenesis mechanisms. In this study, leveraging publicly available genetic data, we conducted an extensive two-sample MR analysis to explore the causal link between 731 immune cell signatures and IgAN risk.<b>Methods </b>This analysis encompassed four distinct types of immune signatures, namely, median fluorescence intensities, relative cells, absolute cells, and morphological parameters. Rigorous sensitivity analyses were implemented to validate the robustness of our findings, assess heterogeneity, and identify horizontal pleiotropy. In addition, flow cytometry was performed on peripheral blood of clinical IgAN patients as well as healthy controls to validate the immunophenotypes.<b>Results </b>Employing the inverse variance-weighted (IVW) method, our MR analysis, with false discovery rate (FDR) correction, revealed a causal relationship between CD3 expression on effector memory (EM) CD4⁺ cells and IgAN risk (odds ratio (OR) 1.042; 95% CI=1.018–1.067; <i>P</i>=5.16×10⁻⁴; and PFDR=0.189). Additionally, we identified CD4 expression on central memory (CM) CD4⁺ cells as a protective factor against IgAN (OR 0.935; 95% CI=0.901–0.970; <i>P</i>=3.54×10⁻⁴; and PFDR=0.189). Analysis via flow cytometry revealed that MFI of CD3 on EM CD4⁺ was higher in the peripheral blood of IgAN patients compared with normal controls, whereas the MFI of CD4+ on CM CD4⁺ was lower.<b>Conclusion </b>This study has illustrated the intricate relationship between immunophenotypes and IgAN, offering new avenues for potential therapeutic targets in future research.