Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population
Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population
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DOI：
10.1126/scitranslmed.3000237
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发表时间：
2009-11-04
影响因子：
17.1
通讯作者：
Shinomiya, Nariyoshi
中科院分区：
文献类型：
--
作者：
Matsuo, Hirotaka;Takada, Tappei;Shinomiya, Nariyoshi
高尿酸血症引起的痛风是一种常见的遗传性疾病，可引起急性关节炎。ABCG 2/BCRP基因位于染色体4 q上的痛风易感基因座，已被最近的血清尿酸浓度和痛风的全基因组关联研究所确定。尿酸转运试验表明ABCG 2是一种高容量的尿酸分泌转运蛋白。对90例高尿酸血症患者的ABCG 2基因进行测序，发现了几种非功能性ABCG 2突变，包括Q126 X。对739名个体的数量性状位点分析表明，ABCG 2的一种常见功能障碍变体Q141 K会增加血清尿酸。Q126 X与Q141 K的疾病单倍型不同，增加了痛风风险，优势比为5.97。此外，10%的痛风患者（159例中的16例）具有导致ABCG 2功能降低超过75%的基因型组合（比值比，25.8）。我们的研究结果表明，ABCG 2的非功能性变体基本上阻断了肠道和肾脏的尿酸盐排泄，并导致痛风。
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.