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