Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

Nakayama, Akiyoshi; Matsuo, Hirotaka; Nakaoka, Hirofumi; Nakamura, Takahiro; Nakashima, Hiroshi; Takada, Yuzo; Oikawa, Yuji; Takada, Tappei; Sakiyama, Masayuki; Shimizu, Seiko; Kawamura, Yusuke; Chiba, Toshinori; Abe, Junko; Wakai, Kenji; Kawai, Shinya; Okada, Rieko; Tamura, Takashi; Shichijo, Yuka; Akashi, Akira; Suzuki, Hiroshi; Hosoya, Tatsuo; Sakurai, Yoshinori; Ichida, Kimiyoshi; Shinomiya, Nariyoshi

doi:10.1038/srep05227

Cited by 76 publications

(68 citation statements)

References 20 publications

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“…We and other groups [5][6][7][8][9] recently reported gout/ hyperuricaemia to have relatively strong genetic risk factors. More recently, and for the first time, we performed a GWAS with only clinically defined Japanese male gout cases in which 16 single nucleotide polymorphisms (SNPs) were replicated, and five gout-risk loci were identified including two novel loci (MYL2-CUX2 and CNIH-2).…”

Section: Introductionmentioning

confidence: 68%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

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ObjectiveA genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.MethodsPutative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.ResultsIn addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8).ConclusionsOur findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

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Section: Introductionmentioning

confidence: 68%

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

et al. 2016

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“…In a cohort of 5,005 Japanese participants, the ABCG2 genotype had a greater effect on SUA than did other epidemiological risk factors for hyperuricemia, such as body mass index and alcohol intake (142). This observation needs to be repeated in other populations; however, it suggests a broad utility for small-molecule therapies capable of correcting the expression defects in specific ABCG2 mutations (136).…”

Section: Abcg2 and Mrp4mentioning

confidence: 96%

The Molecular Physiology of Uric Acid Homeostasis

Mandal

Mount²

2015

Annu. Rev. Physiol.

426

331

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Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.

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“…ATP-binding cassette transporter, subfamily G, member 2 ( ABCG2/BCRP ) is a high-capacity urate transporter2 and expresses in both intestine3 and kidney4. We and others previously demonstrated that ABCG2 dysfunction by its common variants causes gout256 and hyperuricemia27 by decreasing urate excretion. However, the evaluation of intestinal urate excretion in humans is very difficult due to urate degradation by intestinal bacterial flora.…”

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confidence: 99%

Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2

Matsuo

Tsunoda²,

Ooyama³

et al. 2016

Sci Rep

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To clarify the physiological and pathophysiological roles of intestinal urate excretion via ABCG2 in humans, we genotyped ABCG2 dysfunctional common variants, Q126X (rs72552713) and Q141K (rs2231142), in end-stage renal disease (hemodialysis) and acute gastroenteritis patients, respectively. ABCG2 dysfunction markedly increased serum uric acid (SUA) levels in 106 hemodialysis patients (P = 1.1 × 10−4), which demonstrated the physiological role of ABCG2 for intestinal urate excretion because their urate excretion almost depends on intestinal excretion via ABCG2. Also, ABCG2 dysfunction significantly elevated SUA in 67 acute gastroenteritis patients (P = 6.3 × 10−3) regardless of the degree of dehydration, which demonstrated the pathophysiological role of ABCG2 in acute gastroenteritis. These findings for the first time show ABCG2-mediated intestinal urate excretion in humans, and indicates the physiological and pathophysiological importance of intestinal epithelium as an excretion pathway besides an absorption pathway. Furthermore, increased SUA could be a useful marker not only for dehydration but also epithelial impairment of intestine.

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Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

Cited by 76 publications

References 20 publications

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

The Molecular Physiology of Uric Acid Homeostasis

Hyperuricemia in acute gastroenteritis is caused by decreased urate excretion via ABCG2

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