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Clinical Research and Public HealthIn-Press PreviewGeneticsMetabolismNephrology Open Access | 10.1172/JCI186633

Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12

Wataru Fujii,1 Osamu Yamazaki,1 Daigoro Hirohama,1 Ken Kaseda,1 Emiko Kuribayashi-Okuma,1 Motonori Tsuji,2 Makoto Hosoyamada,3 Yuta Kochi,4 and Shigeru Shibata1

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Fujii, W. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Yamazaki, O. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Hirohama, D. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Kaseda, K. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Kuribayashi-Okuma, E. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Tsuji, M. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Hosoyamada, M. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Kochi, Y. in: JCI | PubMed | Google Scholar

1Division of Nephrology, Teikyo University, Tokyo, Japan

2Institute of Molecular Function, Misato-shi, Japan

3Laboratory of Human Physiology and Pathology, Teikyo University, Tokyo, Japan

4Department of Genomic Function and Diversity, Institute of Science Tokyo, Tokyo, Japan

Find articles by Shibata, S. in: JCI | PubMed | Google Scholar

Published March 18, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186633.
Copyright © 2025, Fujii et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 18, 2025 - Version history
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Abstract

BACKGROUND. Hyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear. METHODS. We evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1). RESULTS. The index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that SGK1, induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 eQTL rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia. CONCLUSION. URAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia. FUNDING. ACRO Research Grants of Teikyo University; JSPS; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.

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