Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population.
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.
Matsuo
Hirotaka
H
Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan. hmatsuo@ndmc.ac.jp
Takada
Tappei
T
Ichida
Kimiyoshi
K
Nakamura
Takahiro
T
Nakayama
Akiyoshi
A
Ikebuchi
Yuki
Y
Ito
Kousei
K
Kusanagi
Yasuyoshi
Y
Chiba
Toshinori
T
Tadokoro
Shin
S
Takada
Yuzo
Y
Oikawa
Yuji
Y
Inoue
Hiroki
H
Suzuki
Koji
K
Okada
Rieko
R
Nishiyama
Junichiro
J
Domoto
Hideharu
H
Watanabe
Satoru
S
Fujita
Masanori
M
Morimoto
Yuji
Y
Naito
Mariko
M
Nishio
Kazuko
K
Hishida
Asahi
A
Wakai
Kenji
K
Asai
Yatami
Y
Niwa
Kazuki
K
Kamakura
Keiko
K
Nonoyama
Shigeaki
S
Sakurai
Yutaka
Y
Hosoya
Tatsuo
T
Kanai
Yoshikatsu
Y
Suzuki
Hiroshi
H
Hamajima
Nobuyuki
N
Shinomiya
Nariyoshi
N
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*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins