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Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout
Owen M Woodward1, Anna Köttgen, Josef Coresh
1Department of Physiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Summary
This study identifies ATP-binding cassette, subfamily G, 2 (ABCG2) as a novel urate transporter in the kidneys. A common genetic variant (rs2231142) in ABCG2 significantly impacts urate levels and is a major cause of gout.
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Genome-wide association studies (GWAS) identify SNPs linked to complex diseases but not gene function or causality.
- Previous GWAS identified SNPs on chromosome 4 associated with serum urate levels and gout.
- The specific gene and mechanism underlying this association remained unclear.
Purpose of the Study:
- To identify the gene responsible for urate level regulation in the identified GWAS region.
- To functionally characterize the role of the identified gene in urate transport.
- To establish the causal relationship between a specific SNP and gout risk.
Main Methods:
- Functional assays were performed to test the urate transport activity of ATP-binding cassette, subfamily G, 2 (ABCG2).
- Site-directed mutagenesis was used to introduce the Q141K mutation (rs2231142) into ABCG2.
- A population-based study of 14,783 individuals analyzed the association of rs2231142 with urate levels and gout.
Main Results:
- ABCG2 was identified as a novel urate efflux transporter.
- Native ABCG2 is localized to the brush border membrane of kidney proximal tubule cells, mediating renal urate secretion.
- The Q141K mutation (rs2231142) significantly reduced urate transport by 53% and was strongly associated with lower urate levels and increased gout risk in both white and black populations.
- This variant accounts for at least 10% of gout cases in whites.
Conclusions:
- ABCG2 is a key mediator of renal urate secretion and a significant determinant of serum urate levels.
- The common SNP rs2231142 in ABCG2 is a causal variant for gout.
- ABCG2 represents a promising therapeutic target for gout treatment.
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