Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population

被引：349

作者：

Matsuo, Hirotaka ^{[1
]}

Takada, Tappei ^{[2
]}

Ichida, Kimiyoshi ^{[3
,4
]}

Nakamura, Takahiro ^{[5
,6
]}

Nakayama, Akiyoshi ^{[1
,7
]}

Ikebuchi, Yuki ^{[2
]}

Ito, Kousei ^{[2
]}

Kusanagi, Yasuyoshi ^{[1
]}

Chiba, Toshinori ^{[1
]}

Tadokoro, Shin ^{[1
]}

Takada, Yuzo ^{[8
]}

Oikawa, Yuji ^{[9
]}

Inoue, Hiroki ^{[1
]}

Suzuki, Koji ^{[10
]}

Okada, Rieko ^{[11
]}

Nishiyama, Junichiro ^{[12
]}

Domoto, Hideharu ^{[13
]}

Watanabe, Satoru ^{[14
]}

Fujita, Masanori ^{[14
]}

Morimoto, Yuji ^{[1
]}

Naito, Mariko ^{[11
]}

Nishio, Kazuko ^{[11
]}

Hishida, Asahi ^{[11
]}

Wakai, Kenji ^{[11
]}

Asai, Yatami ^{[15
]}

Niwa, Kazuki ^{[9
]}

Kamakura, Keiko ^{[16
]}

Nonoyama, Shigeaki ^{[17
]}

Sakurai, Yutaka ^{[18
]}

Hosoya, Tatsuo ^{[4
]}

Kanai, Yoshikatsu ^{[19
]}

Suzuki, Hiroshi ^{[2
]}

Hamajima, Nobuyuki ^{[11
]}

Shinomiya, Nariyoshi ^{[1
]}

机构：

[1] Natl Def Med Coll, Dept Integrat Physiol & Bionano Med, Saitama 3598513, Japan

[2] Univ Tokyo, Dept Pharm, Tokyo Univ Hosp, Fac Med, Tokyo 1138655, Japan

[3] Tokyo Univ Pharm & Life Sci, Dept Pathophysiol, Tokyo 1920392, Japan

[4] Jikei Univ, Sch Med, Div Kidney & Hypertens, Dept Internal Med, Tokyo 1058461, Japan

[5] Natl Def Med Coll, Math Lab, Premed Course, Saitama 3598513, Japan

[6] Inst Phys & Chem Res, Lab Stat Anal, Ctr Genom Med, Tokyo 1088639, Japan

[7] Japan Air Self Def Force, Kagoshima 8961411, Japan

[8] Natl Def Med Coll, Dept Forens Med, Saitama 3598513, Japan

[9] Toho Univ, Dept Biol, Fac Sci, Chiba 2748510, Japan

[10] Fujita Hlth Univ, Sch Hlth Sci, Dept Publ Hlth, Aichi 4701192, Japan

[11] Nagoya Univ, Grad Sch Med, Dept Prevent Med Biostat & Med Decis Making, Aichi 4668550, Japan

[12] Hosp Yokosuka, Kanagawa 2370071, Japan

[13] Japan Maritime Self Def Force, Med Serv Unit Kure, Hiroshima 7378554, Japan

[14] Natl Def Med Coll, Res Inst, Div Environm Med, Saitama 3598513, Japan

[15] Seirei Social Welf Community, Shizuoka 4300946, Japan

[16] Natl Def Med Coll, Dept Internal Med, Saitama 3598513, Japan

[17] Natl Def Med Coll, Dept Pediat, Saitama 3598513, Japan

[18] Natl Def Med Coll, Dept Prevent Med & Publ Hlth, Saitama 3598513, Japan

[19] Osaka Univ, Grad Sch Med, Dept Pharmacol, Div Biosyst Pharmacol, Suita, Osaka 5650871, Japan

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2009年 / 1卷 / 05期

关键词：

CANCER RESISTANCE PROTEIN; PAROXYSMAL DYSTONIC CHOREOATHETOSIS; URIC-ACID LEVEL; MULTIDRUG RESISTANCE; TRANSPORTER ABCG2; ANION-EXCHANGER; CELL LINES; HYPERURICEMIA; DISEASE; DIETARY;

D O I：

10.1126/scitranslmed.3000237

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：8

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