ABCG2/BCRP DYSFUNCTION AS A MAJOR CAUSE OF GOUT
ABCG2/BCRP DYSFUNCTION AS A MAJOR CAUSE OF GOUT
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DOI：
10.1080/15257770.2011.633954
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发表时间：
2011-01-01
影响因子：
1.3
通讯作者：
Shinomiya, Nariyoshi
中科院分区：
文献类型：
--
作者：
Matsuo, Hirotaka;Takada, Tappei;Shinomiya, Nariyoshi
最近的全基因组关联研究表明，血清尿酸（SUA）水平与ABCG 2/BCRP基因有关，该基因位于全基因组连锁研究揭示的痛风易感位点。结合ABCG 2的特性，我们假设ABCG 2转运尿酸盐，其功能障碍导致高尿酸血症和痛风。转运试验显示尿酸盐通过ABCG 2进行ATP依赖性转运。动力学分析表明，ABCG 2介导高容量的尿酸盐运输（Km：8.24 +/- 1.44 mM），即使在高尿酸盐条件下。90例日本高尿酸血症患者的ABCG 2突变分析检测到6个非同义突变，包括5个功能失调的变异体。然后检查了两个相对频繁的功能失调变体Q126 X和Q141 K。对739个日本个体的数量性状基因座分析表明，随着Q141 K次要等位基因数量的增加，Q141 K增加了SUA（p = 6.60 × 10（-5））。单倍型频率分析表明，没有Q126 X和Q141 K同时存在于一个单倍型。由于Q126 X和Q141 K分别属于非功能性和半功能性单倍型，因此将它们的基因型组合分为四个功能组。对161名男性痛风患者和865名男性对照者的相关研究显示，所有ABCG 2功能障碍的人都增加了痛风风险，尤其是那些
Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 +/- 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 x 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with