image: Image Caption: Flowchart of study. Image link: https://ars.els-cdn.com/content/image/1-s2.0-S2352304225000364-gr1_lrg.jpg
Credit: Genes & Diseases
A recent study published in Genes & Diseases reveals new insights into the relationship between immune cell characteristics, blood metabolites, and the risk of urolithiasis. Using Mendelian randomization (MR) and mediation analysis, the research highlights how genetically predicted blood metabolites mediate the association between specific immune cell profiles and the development of urinary stones. The findings shed light on potential pathogenic mechanisms and suggest novel therapeutic targets for this widespread and recurrent condition.
Urolithiasis, characterized by the formation of urinary stones, affects approximately 10% to 15% of the global population, with prevalence on the rise. It is influenced by multiple factors, including immune dysregulation and metabolic disturbances. In this study, researchers employed a two-sample Mendelian randomization approach to assess the causal relationship between immune cell features, blood metabolites, and urolithiasis risk. The study involved data from 488,346 individuals, including 6,223 cases of urolithiasis and 482,123 controls, and utilized genetic instruments derived from Genome-Wide Association Studies (GWAS).
The analysis identified 10 immune cell characteristics significantly associated with urolithiasis, including markers from the B cell panel, Treg cell panel, and CDC panel. Among these, IgD-CD24-% lymphocyte, CD24 on transitional B cells, CD25 on IgD+ CD38- naïve, CD4 Treg % T cell, and activated and resting Treg AC were found to increase the risk of urolithiasis. On the other hand, HLA DR on plasmacytoid DC, HLA DR on DC, and HLA DR on B cells were identified as protective factors. Notably, the reverse MR analysis did not support a causal effect of urolithiasis on immune cell characteristics, indicating a unidirectional relationship.
Further analysis revealed 13 metabolites linked with urolithiasis, including lipids, amino acids, carbohydrates, and metabolite ratios. Among these, glycolithocholate and 4-hydroxychlorothalonil (4-OH-CHT) were associated with increased risk, while stearidonate and sphingomyelin were associated with a reduced risk. Importantly, glycolithocholate and 1-oleoyl-2-linoleoyl-GPE positively mediated the link between B cell traits and urolithiasis, while 4-OH-CHT negatively mediated the association between CD4 Treg % T cells and urolithiasis.
These findings emphasize that blood metabolites play a significant role in the immune-mediated formation of urinary stones. By uncovering the metabolic pathways involved, the study not only enhances the understanding of urolithiasis pathogenesis but also proposes new biomarkers for risk assessment. Furthermore, it suggests that targeting immune-metabolic interactions could be a promising strategy for preventing and managing urolithiasis.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Chengcheng Wei, Jiattai He, Jun Wen, Shunyao Wang, Mengjia Shi, Juan Hu, Huanhuan Tan, Jinjun Guo, Xiaosong Li, Genetically predicted blood metabolites mediate the association between immune cell characteristics and urolithiasis: A Mendelian randomization study and mediation analysis, Genes & Diseases, 2025, 101547, https://doi.org/10.1016/j.gendis.2025.101547
Funding Information:
Innovation and Development Joint Fund of Chongqing Natural Science Foundation of China CST-B2023NSCQ-LZX0099
Chongqing Science and Health Joint Medical High-end Talent Project (China) 2022GDRC012
Science and Technology Research Program of Chongqing Municipal Education Commission of China KJZD-K202100402
CQMU Program for Youth Innovation in Future Medicine (Chongqing, China) W0073
Journal
Genes & Diseases