Identification of ABCG2 dysfunction as a major factor contributing to gout

Area of Science:

• Genetics
• Biochemistry
• Human Disease

Background:

• The ATP-binding cassette, subfamily G, member 2 (ABCG2) gene is implicated in gout susceptibility and serum uric acid levels.
• ABCG2 functions as a transporter for nucleotide analogs similar to urate and possesses common reduced-functionality variants.
• ABCG2 is a potential urate secretion transporter and a candidate gene for gout.

Purpose of the Study:

• To identify candidate mutations in the ABCG2 gene associated with hyperuricemia and gout.
• To investigate the functional impact of ABCG2 variants on urate transport.
• To determine the association between ABCG2 gene variants and gout risk in the Japanese population.

Main Methods:

• Mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia.
• Assessment of ATP-dependent urate transport for identified ABCG2 variants.
• Haplotype frequency analysis and association study in 161 male gout patients and 865 male controls.
• Genotyping of dysfunctional ABCG2 variants in 2,150 Japanese individuals.

Main Results:

• Six non-synonymous mutations were identified in the ABCG2 gene.
• Five variants showed reduced or eliminated ATP-dependent urate transport, with Q126X and Q141K being frequent.
• Individuals with dysfunctional ABCG2 exhibited significantly increased gout risk, especially those with ≤1/4 function (OR, 25.8).
• Over 50% of the Japanese population studied carried at least one dysfunctional ABCG2 variant.

Conclusions:

• Combinations of dysfunctional ABCG2 variants are a major contributing factor to gout in Japanese patients.
• Reduced urate transport function of ABCG2 variants is strongly associated with gout development.
• The high prevalence of dysfunctional ABCG2 variants highlights their significant role in the pathogenesis of gout in Japan.