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ABCG2/BCRP dysfunction as a major cause of gout
Hirotaka Matsuo1, Tappei Takada, Kimiyoshi Ichida
1Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan. hmatsuo@ndmc.ac.jp
Nucleosides, Nucleotides & Nucleic Acids
|December 3, 2011
Summary
Dysfunctional ABCG2 transporter significantly increases gout risk, particularly with combined mutations. This finding offers new strategies for preventing and treating gout in at-risk individuals.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Clinical Medicine
Background:
- Genome-wide studies link serum uric acid (SUA) levels to the ABCG2/BCRP gene.
- ABCG2 is located in a known gout-susceptibility locus, suggesting a role in urate transport.
Purpose of the Study:
- To investigate if ABCG2 transports urate and if its dysfunction contributes to hyperuricemia and gout.
- To analyze the impact of ABCG2 mutations on SUA levels and gout risk.
Main Methods:
- In vitro transport assays to confirm ATP-dependent urate transport by ABCG2.
- Kinetic analysis to determine urate transport capacity.
- Mutation analysis in hyperuricemia patients and association studies in gout patients and controls.
- Function-based clinicogenetic (FBCG) analysis of ABCG2 variants.
Main Results:
- ABCG2 mediates high-capacity, ATP-dependent urate transport.
- Five dysfunctional ABCG2 variants were identified in hyperuricemia patients.
- The Q141K variant was associated with increased SUA levels.
- Dysfunctional ABCG2 genotypes, especially those with reduced function (≤1/4), significantly increased gout risk (OR 25.8).
- These high-risk genotypes were found in 10.1% of gout patients versus 0.9% of controls.
Conclusions:
- ABCG2 dysfunction is a major cause of hyperuricemia and gout.
- Combinations of dysfunctional ABCG2 variants are key contributors to gout development.
- FBCG analysis provides a novel approach for identifying and managing individuals at high risk for gout.
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