title: ABCG2 dysfunction increases the risk of renal overload hyperuricemia.
abstract: 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.
authors.affiliation: a Department of Integrative Physiology and Bio-Nano Medicine , National Defense Medical College , Tokorozawa , Saitama , Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.forename: Seiko
authors.initials: S
authors.lastname: Shimizu
authors.forename: Toshinori
authors.initials: T
authors.lastname: Chiba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Takada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D033461:Hyperuricemia / Q000097:blood* / Q000235:genetics*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D014527:Uric Acid / Q000097:blood
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D014527:Uric Acid
keywords: ABC transporters; extra-renal underexcretion type; hyperuricemia/gout; renal urate overload