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GLUT9 as a potential drug target for chronic kidney disease: Drug target validation by a Mendelian randomization study

Journal of Human Genetics volume 68, pages 699–704 (2023)Cite this article

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Abstract

Although chronic kidney disease (CKD) is recognized as a major public health concern, effective treatment strategies have yet to be developed. Identification and validation of drug targets are key issues in the development of therapeutic agents for CKD. Uric acid (UA), a major risk factor for gout, has also been suggested to be a risk factor for CKD, but the efficacy of existing urate-lowering therapies for CKD is controversial. We focused on five uric acid transporters (ABCG2, SLC17A1, SLC22A11, SLC22A12, SLC2A9) as potential drug targets and evaluated the causal association between serum UA levels and estimated glomerular filtration rate (eGFR) using single-SNP Mendelian Randomization. The results showed a causal association between genetically predicted changes in serum UA levels and eGFR when genetic variants were selected from the SLC2A9 locus. Estimation based on a loss-of-function mutation (rs16890979) showed that the changes in eGFR per unit increase in serum UA level was −0.0082 ml/min/1.73 m2 (95% CI −0.014 to −0.0025, P = 0.0051). These results indicate that SLC2A9 may be a novel drug target for CKD that preserves renal function through its urate-lowering effect.

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Data availability

All summary statistics data used in this study are freely available through MR-Base (URL: https://www.mrbase.org/) [26].

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Acknowledgements

The authors thank the participants, staffs, and investigators of the contributing consortiums, including CKDGen, UK biobank and Bristol University for developing MR base platform. M.U. thank ASCA Corporation (http://www.asca-co.com/english_site/) for proofreading a draft of this manuscript.

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Authors and Affiliations

  1. Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan

    Masatoshi Ueda, Kenji Fukui, Akira Matsuo, Tomohiko Sasase, Jun Nishiu & Mutsuyoshi Matsushita

  2. StaGen Co., Ltd, Tokyo, Japan

    Naoyuki Kamatani & Shigeo Kamitsuji

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  1. Masatoshi Ueda
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Contributions

MU designed research, performed statistical analysis, and wrote the manuscript. MU, KF, SK, and NK discussed and interpreted results. AM, JN, TS, MM, SK, and NK provided critical feedback and revision of this work. All of the authors approved the final version of this work.

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Correspondence to Masatoshi Ueda.

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Competing interests

MU, KF, AM, JN TS, and MM are employees of JAPAN TOBACCO INC. SK and NK has received consulting fees from JAPAN TOBACCO INC.

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Ueda, M., Fukui, K., Kamatani, N. et al. GLUT9 as a potential drug target for chronic kidney disease: Drug target validation by a Mendelian randomization study. J Hum Genet 68, 699–704 (2023). https://doi.org/10.1038/s10038-023-01168-8

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