ABCG2 DYSFUNCTION INCREASES THE RISK OF RENAL OVERLOAD HYPERURICEMIA
ABCG2 DYSFUNCTION INCREASES THE RISK OF RENAL OVERLOAD HYPERURICEMIA
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DOI：
10.1080/15257770.2013.866679
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发表时间：
2014-01-01
影响因子：
1.3
通讯作者：
Ichida, Kimiyoshi
中科院分区：
文献类型：
--
作者：
Matsuo, Hirotaka;Takada, Tappei;Ichida, Kimiyoshi
ATP结合盒转运蛋白，亚家族G，成员2（ABCG 2/BCRP）被确定为高容量尿酸盐输出蛋白，其功能障碍与血清尿酸水平和痛风/高尿酸血症风险相关。通常，高尿酸血症仅根据肾尿酸盐排泄而不考虑肠排泄等肾外途径，分为尿酸盐“生成过剩型”、“排泄不足型”和“混合型”。在这项研究中，我们调查了ABCG 2功能障碍对人体尿酸盐处理的影响和高尿酸血症的机制。尿酸盐处理的临床参数，包括尿尿酸盐排泄（UUE）在644例日本男性高尿酸血症门诊患者进行了检查。通过两种常见的ABCG 2变异体（非功能性Q126 X（rs72552713）和半功能性Q141 K（rs 2231142））的基因型组合来评估其ABCG 2功能障碍的严重程度。与ABCG 2功能障碍导致肾尿酸排泄减少的一般理解相反，ABCG 2功能障碍显著增加UUE（P = 3.60 x 10（-10））。轻度、中度和重度ABCG 2功能障碍显著增加了“过度生产型”高尿酸血症（包括过度生产型和混合型）的风险，其风险比分别为1.36、1.66和2.35，提示ABCG 2的常见功能障碍变异体减少了肾外尿酸排泄（包括肠道排泄）并引起高尿酸血症。因此，目前高尿酸血症概念中的“过度生成型”应更名为“肾超负荷型”，这是由“肾外尿酸排泄不足”和真正的“尿酸过度生成”两种不同机制引起的。“我们的新概念将导致更准确的诊断和更有效的治疗策略，高尿酸血症和痛风。
ATP-binding cassette transporter, sub-family G, member 2 (ABCG2/BCRP) is identified as a high-capacity urate exporter, and its dysfunction has an association with serum uric acid levels and gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate "overproduction type," "underexcretion type," and "combined type" based on only renal urate excretion, without considering an extra-renal pathway such as gut excretion. In this study, we investigated the effects of ABCG2 dysfunction on human urate handling and the mechanism of hyperuricemia.Clinical parameters for urate handling including urinary urate excretion (UUE) were examined in 644 Japanese male outpatients with hyperuricemia. The severity of their ABCG2 dysfunction was estimated by genotype combination of two common ABCG2 variants, nonfunctional Q126X (rs72552713) and half-functional Q141K (rs2231142).Contrary to the general understanding that ABCG2 dysfunction leads to decreased renal urate excretion, UUE was significantly increased by ABCG2 dysfunction (P = 3.60 x 10(-10)). Mild, moderate, and severe ABCG2 dysfunctions significantly raised the risk of "overproduction" hyperuricemia including overproduction type and combined type, conferring risk ratios of 1.36, 1.66, and 2.35, respectively.The present results suggest that common dysfunctional variants of ABCG2 decrease extra-renal urate excretion including gut excretion and cause hyperuricemia. Thus, "overproduction type" in the current concept of hyperuricemia should be renamed "renal overload type," which is caused by two different mechanisms, "extra-renal urate underexcretion" and genuine "urate overproduction."Our new concept will lead to a more accurate diagnosis and more effective therapeutic strategy for hyperuricemia and gout.