title: Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population.
abstract: Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan. hmatsuo@ndmc.ac.jp
authors.forename: Hirotaka
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authors.lastname: Matsuo
authors.forename: Tappei
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authors.lastname: Takada
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authors.lastname: Ichida
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authors.lastname: Nakamura
authors.forename: Akiyoshi
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authors.lastname: Ikebuchi
authors.forename: Kousei
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authors.forename: Toshinori
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authors.lastname: Tadokoro
authors.forename: Yuzo
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authors.lastname: Takada
authors.forename: Yuji
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authors.lastname: Oikawa
authors.forename: Hiroki
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authors.lastname: Inoue
authors.forename: Koji
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authors.forename: Rieko
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authors.lastname: Okada
authors.forename: Junichiro
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authors.lastname: Nishiyama
authors.forename: Hideharu
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authors.lastname: Domoto
authors.forename: Satoru
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authors.lastname: Watanabe
authors.forename: Masanori
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authors.lastname: Fujita
authors.forename: Yuji
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authors.lastname: Morimoto
authors.forename: Mariko
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authors.lastname: Naito
authors.forename: Kazuko
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authors.lastname: Nishio
authors.forename: Asahi
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authors.lastname: Hishida
authors.forename: Kenji
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authors.lastname: Wakai
authors.forename: Yatami
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authors.lastname: Asai
authors.forename: Kazuki
authors.initials: K
authors.lastname: Niwa
authors.forename: Keiko
authors.initials: K
authors.lastname: Kamakura
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hamajima
authors.forename: Nariyoshi
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authors.lastname: Shinomiya
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D005828:Genetics, Population; D005838:Genotype; D006073:Gout / Q000235:genetics*; D006801:Humans; D007564:Japan; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins