Exploring the causal association between circulating leukocyte count and IgA nephropathy based on two-sample Mendelian randomization: possible role of transitional B cells.

Background: To examine the causal association between genetically predicted circulating leukocyte counts and IgA nephropathy.

Methods: A two-sample Mendelian randomization (MR) design was used. The exposures were the neutrophil, lymphocyte (with subsequent analyses for memory B-cell %lymphocyte, IgD^- CD38^br %lymphocyte, IgD⁺ CD38^br %lymphocyte, CD24⁺ CD27⁺ %lymphocyte, Sw mem %lymphocyte, transitional %lymphocyte, and naïve-mature B-cell %lymphocyte), monocyte, basophil, and eosinophil counts. The outcome was IgA nephropathy. Analysis was conducted using the inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. The Cochran's Q-test and MR-Egger regression were used to assess heterogeneity and horizontal pleiotropy, respectively. The robustness of the results was tested using MR-PRESSO and leave-one-out analyses.

Results: The genetic prediction results showed causal associations between the neutrophil counts and IgA nephropathy (OR = 2.62, 95%CI 2.47-2.77, P < 0.001) and between the lymphocyte counts and IgA nephropathy (OR = 0.76, 95%CI 0.58-0.99, P = 0.04). Monocyte, basophil, and eosinophil counts showed no causal associations with IgA nephropathy. The supplementary genetic prediction analyses showed a causal association between transitional %lymphocytes and IgA nephropathy (OR = 0.58, 95%CI 0.39-0.87, P = 0.008). Cochran's Q test revealed heterogeneity for the neutrophil, lymphocyte, monocyte, eosinophil, transitional %lymphocytes, and count analyses (all P < 0.05), but the MR-Egger test revealed no pleiotropy. After removing the outliers, the associations remained the same.

Conclusion: Causal associations were observed between neutrophil and lymphocyte counts as exposures and IgA nephropathy as outcome. Among lymphocytes, transitional B cells could be involved in the pathogenesis of IgA nephropathy. Attention should be paid to neutrophil and lymphocyte counts in future studies on IgA nephropathy.