TY - JOUR
T1 - Common defects of ABCG2, a high-capacity urate exporter, cause gout
T2 - A function-based genetic analysis in a Japanese population
AU - Matsuo, Hirotaka
AU - Takada, Tappei
AU - Ichida, Kimiyoshi
AU - Nakamura, Takahiro
AU - Nakayama, Akiyoshi
AU - Ikebuchi, Yuki
AU - Ito, Kousei
AU - Kusanagi, Yasuyoshi
AU - Chiba, Toshinori
AU - Tadokoro, Shin
AU - Takada, Yuzo
AU - Oikawa, Yuji
AU - Inoue, Hiroki
AU - Suzuki, Koji
AU - Okada, Rieko
AU - Nishiyama, Junichiro
AU - Domoto, Hideharu
AU - Watanabe, Satoru
AU - Fujita, Masanori
AU - Morimoto, Yuji
AU - Naito, Mariko
AU - Nishio, Kazuko
AU - Hishida, Asahi
AU - Wakai, Kenji
AU - Asai, Yatami
AU - Niwa, Kazuki
AU - Kamakura, Keiko
AU - Nonoyama, Shigeaki
AU - Sakurai, Yutaka
AU - Hosoya, Tatsuo
AU - Kanai, Yoshikatsu
AU - Suzuki, Hiroshi
AU - Hamajima, Nobuyuki
AU - Shinomiya, Nariyoshi
PY - 2009/11/4
Y1 - 2009/11/4
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.3000237
DO - 10.1126/scitranslmed.3000237
M3 - Article
C2 - 20368174
AN - SCOPUS:77952845866
SN - 1946-6234
VL - 1
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 5
M1 - 5ra11
ER -