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- CD38br %lymphocyte, IgD+ CD38br %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.