Matsuo Hirotaka, Takada Tappei, Nakayama Akiyoshi, Shimizu Toru, Sakiyama Masayuki, Shimizu Seiko, Chiba Toshinori, Nakashima Hiroshi, Nakamura Takahiro, Takada Yuzo, Sakurai Yutaka, Hosoya Tatsuo, Shinomiya Nariyoshi, Ichida Kimiyoshi
a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
Nucleosides Nucleotides Nucleic Acids. 2014;33(4-6):266-74. doi: 10.1080/15257770.2013.866679.
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=3.60×10(-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.
ATP结合盒转运体G亚家族成员2（ABCG2/BCRP）被确定为一种高容量尿酸盐转运体，其功能障碍与血清尿酸水平及痛风/高尿酸血症风险相关。一般来说，高尿酸血症仅基于肾脏尿酸排泄被分为尿酸“生成过多型”“排泄减少型”和“混合型”，而未考虑肠道排泄等肾外途径。在本研究中，我们调查了ABCG2功能障碍对人体尿酸处理的影响以及高尿酸血症的发病机制。对644名日本男性高尿酸血症门诊患者进行了包括尿尿酸排泄（UUE）在内的尿酸处理临床参数检查。通过两种常见ABCG2变异体（无功能的Q126X（rs72552713）和半功能的Q141K（rs2231142））的基因型组合来评估其ABCG2功能障碍的严重程度。与ABCG2功能障碍导致肾脏尿酸排泄减少的普遍认识相反，ABCG2功能障碍使UUE显著增加（P = 3.60×10⁻¹⁰）。轻度、中度和重度ABCG2功能障碍显著增加了“生成过多型”高尿酸血症（包括生成过多型和混合型）的风险，风险比分别为1.36、1.66和2.35。目前的结果表明，ABCG2常见功能障碍变异体减少包括肠道排泄在内的肾外尿酸排泄并导致高尿酸血症。因此，当前高尿酸血症概念中的“生成过多型”应重新命名为“肾脏超负荷型”，其由两种不同机制引起，即“肾外尿酸排泄减少”和真正的“尿酸生成过多”。我们的新概念将为高尿酸血症和痛风带来更准确的诊断和更有效的治疗策略。
