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      Decreased extra-renal urate excretion is a common cause of hyperuricemia

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          Abstract

          ABCG2, also known as BCRP, is a high-capacity urate exporter, the dysfunction of which raises gout/hyperuricemia risk. Generally, hyperuricemia has been classified into urate 'overproduction type' and/or 'underexcretion type' based solely on renal urate excretion, without considering an extra-renal pathway. Here we show that decreased extra-renal urate excretion caused by ABCG2 dysfunction is a common mechanism of hyperuricemia. Clinical parameters, including urinary urate excretion, are examined in 644 male outpatients with hyperuricemia. Paradoxically, ABCG2 export dysfunction significantly increases urinary urate excretion and risk ratio of urate overproduction. Abcg2-knockout mice show increased serum uric acid levels and renal urate excretion, and decreased intestinal urate excretion. Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes—'extra-renal urate underexcretion' and genuine 'urate overproduction'—providing a new concept valuable for the treatment of hyperuricemia and gout.

          Abstract

          Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichida et al. show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.

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          Most cited references28

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          Molecular identification of a renal urate anion exchanger that regulates blood urate levels.

          Urate, a naturally occurring product of purine metabolism, is a scavenger of biological oxidants implicated in numerous disease processes, as demonstrated by its capacity of neuroprotection. It is present at higher levels in human blood (200 500 microM) than in other mammals, because humans have an effective renal urate reabsorption system, despite their evolutionary loss of hepatic uricase by mutational silencing. The molecular basis for urate handling in the human kidney remains unclear because of difficulties in understanding diverse urate transport systems and species differences. Here we identify the long-hypothesized urate transporter in the human kidney (URAT1, encoded by SLC22A12), a urate anion exchanger regulating blood urate levels and targeted by uricosuric and antiuricosuric agents (which affect excretion of uric acid). Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12. Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution.
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            SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.

            Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
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              Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study.

              Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5.0 x 10(-8)) or the Rotterdam cohort (p<1.0 x 10(-7)) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7.0 x 10(-168) and 2.9 x 10(-18) for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2.5 x 10(-60) and 9.8 x 10(-4)), and rs1165205 in SLC17A3 (p=3.3 x 10(-26) and 0.33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0.59 per T allele, 95% CI 0.52-0.68, p=7.0 x 10(-14)), rs2231142 (1.74, 1.51-1.99, p=3.3 x 10(-15)), and rs1165205 (0.85, 0.77-0.94, p=0.002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1.71, 1.06-2.77, p=0.028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272-351 mumol/L in the Framingham cohort, 269-386 mumol/L in the Rotterdam cohort, and 303-426 mumol/L in white participants of the ARIC study) and gout (frequency 2-13% in the Framingham cohort, 2-8% in the Rotterdam cohort, and 1-18% in white participants in the ARIC study). We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                03 April 2012
                : 3
                : 764
                Affiliations
                [1 ]simpleDepartment of Pathophysiology, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan.
                [2 ]simpleDivision of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine , 3-19-18 Shinbashi, Minato-ku, Tokyo 105-8471, Japan.
                [3 ]simpleDepartment of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [4 ]simpleDepartment of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
                [5 ]simpleThird Division, Aeromedical Laboratory, Japan Air Self-Defense Force , 2-3 Inariyama, Sayama, Saitama 350-1324, Japan.
                [6 ]simpleMidorigaoka Hospital , 3-13-1 Makami-cho, Takatsuki, Osaka 569-1121, Japan.
                [7 ]simpleDepartment of Preventive Medicine and Public Health, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [8 ]simpleLaboratory for Mathematics, Premedical Course, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [9 ]simpleLaboratory for Statistical Analysis, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN) , 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
                [10 ]simpleLaboratory for Biofunctions, The Central Research Institute, National Defense Medical College , 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
                [11 ]simpleDepartment of Human Physiology and Pathology, Teikyo University School of Pharmaceutical Sciences , 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
                [12 ]These authors contributed equally to this work.
                Author notes
                Article
                ncomms1756
                10.1038/ncomms1756
                3337984
                22473008
                cfd71e61-0182-430f-95bd-e183576ee59a
                Copyright © 2012, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 02 November 2011
                : 20 February 2012
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