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Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study

  • Urology – Original Paper
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Abstract

Purpose

Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis.

Methods

In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results.

Results

91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01–1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00–1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78–0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88–0.98), STAM-binding protein (OR 0.83, 95% CI 0.69–0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger’s intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05.

Conclusions

Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

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Data availability

The original contributions presented in this study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Abbreviations

KSD:

Kidney stone disease

NLR:

Neutrophil-to-lymphocyte ratio

PNL:

Percutaneous nephrolithotomy

FGF-5:

Fibroblast growth factor 5

STAMBP:

STAM-binding protein

GWAS:

Genome-wide association studies

IVs:

Instrumental variable

IVW:

Inverse variance weighted

MR:

Mendelian randomization

MR-PRESSO:

MR-Pleiotropy Residual Sum and Outlier method

OR:

Odds ratio

SNPs:

Single nucleotide polymorphism

DNER:

Delta and Notch-like epidermal growth factor-related receptor

MIP-1α:

Macrophage inflammatory protein 1α

RTECs:

Renal tubular epithelial cells

MCP-1:

Monocyte chemoattractant protein 1

CSF-1:

Colony-stimulating factor 1

CD5L:

CD5 antigen-like

SCFA:

Short chain fatty acids

PSHC:

Potassium sodium hydrogen citrate

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Acknowledgements

We express our gratitude to all SCALLOP Consortium studies for providing open access to the summary association statistics data. Genetic association estimates for kidney stone disease were obtained from the FinnGen consortium (www.finngen.fi/en). We thank all investigators for sharing these data.

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81974092).

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Authors and Affiliations

  1. Department of Urology, Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Liberalization Ave, No. 1095, Wuhan, 430030, China

    Dongfeng Yuan, Junyi Yang, Weisong Wu, Yirixiatijiang Amier, Xianmiu Li, Wenlong Wan, Yisheng Huang, Jiabo Li & Xiao Yu

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  1. Dongfeng Yuan
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Contributions

D.F. Yuan and J.Y. Yang prepared and drafted the manuscript. X. Yu obtained funding for the study and provided critical revision of the manuscript for important intellectual content. W.S. Wu, Y. Amier, X.M. Li, and W.L. Wan assisted in obtaining data for the review article and revised the manuscript. Y.S. Huang and J.B. Li confirmed the authenticity of all the raw data.

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Correspondence to Xiao Yu.

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The authors declare no competing interests.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Our analysis used publicly available GWAS summary statistics. No new data were collected, and no new ethical approval was required.

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Yuan, D., Yang, J., Wu, W. et al. Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study. Int Urol Nephrol 56, 3249–3257 (2024). https://doi.org/10.1007/s11255-024-04084-8

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