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. 2025 Aug;29(8):1032-1044.
doi: 10.1007/s10157-025-02646-3. Epub 2025 Feb 26.

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

Fang Fang  1 , Hong Wang  2 , Jun Luo  2 , Fatong Hong  2
Affiliations

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

Fang Fang et al. Clin Exp Nephrol. 2025 Aug.

Abstract

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.

Keywords: IgA nephropathy; Leukocyte count; Lymphocytes; Mendelian randomization; Neutrophils.

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Conflict of interest statement

Declarations. Conflicts of interest: All the authors have declared no competing interests. Informed consent: Not applicable. Research involving human participants and/or animals: Not applicable. This article does not contain any studies with human participants or animals performed by any of the authors. Consent for publication: Not applicable.

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