NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout

Toshinori Chiba, Hirotaka Matsuo, Yusuke Kawamura, Shushi Nagamori, Takashi Nishiyama, Ling Wei, Akiyoshi Nakayama, Takahiro Nakamura, Masayuki Sakiyama, Tappei Takada, Yutaka Taketani, Shino Suma, Mariko Naito, Takashi Oda, Hiroo Kumagai, Yoshinori Moriyama, Kimiyoshi Ichida, Toru Shimizu, Yoshikatsu Kanai, Nariyoshi Shinomiya

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Objective Serum uric acid (SUA) levels in humans are mainly regulated by urate transporters. Recent genome-wide association studies suggested that common variants of the human sodium-dependent phosphate cotransporter type 1 gene (NPT1/SLC17A1) influence SUA. NPT1 has been reported to mediate urate transport, but its physiologic role in regulating SUA in humans remains unclear. Furthermore, the findings of replication studies of the relationship between NPT1 variants and gout have been inconsistent. The aims of this study were to investigate the effect of NPT1 on gout and to determine its physiologic role.

Methods Five hundred forty-five male Japanese patients with gout and 1,115 male Japanese control subjects were genotyped for rs1165196 (I269T), a common missense variant in NPT1. Analyses of the association between rs1165196 and gout were then conducted, focusing especially on renal underexcretion (RUE) gout. Immunohistochemical analysis and functional analysis using Xenopus oocytes were also performed.

Results Single-nucleotide polymorphism rs1165196 significantly decreased the risk of RUE gout (odds ratio 0.73, P = 0.031) but did not confer a risk for all gout (P = 0.123). The immunohistochemical analysis revealed that human NPT1 is localized to the apical membrane of the renal proximal tubule. The functional analysis using Xenopus oocyte expression systems showed that rs1165196 increases NPT1-mediated urate export.

Conclusion This study showed that NPT1 is a urate exporter located in the renal proximal tubule in humans, and that its common gain-of-function variant, rs1165196, causes RUE gout, a major subtype of gout. These findings enable us to deepen our understanding of the physiologic role of NPT1 as a renal urate exporter as well as its pathophysiologic role in gout.

Original languageEnglish
Pages (from-to)281-287
Number of pages7
JournalArthritis and Rheumatology
Volume67
Issue number1
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

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Gout
Uric Acid
Kidney
Proximal Kidney Tubule
Xenopus
Oocytes
Sodium-Phosphate Cotransporter Proteins
Serum
Genome-Wide Association Study
Single Nucleotide Polymorphism
Odds Ratio
Membranes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Medicine(all)

Cite this

NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. / Chiba, Toshinori; Matsuo, Hirotaka; Kawamura, Yusuke; Nagamori, Shushi; Nishiyama, Takashi; Wei, Ling; Nakayama, Akiyoshi; Nakamura, Takahiro; Sakiyama, Masayuki; Takada, Tappei; Taketani, Yutaka; Suma, Shino; Naito, Mariko; Oda, Takashi; Kumagai, Hiroo; Moriyama, Yoshinori; Ichida, Kimiyoshi; Shimizu, Toru; Kanai, Yoshikatsu; Shinomiya, Nariyoshi.

In: Arthritis and Rheumatology, Vol. 67, No. 1, 01.01.2015, p. 281-287.

Research output: Contribution to journalArticle

Chiba, T, Matsuo, H, Kawamura, Y, Nagamori, S, Nishiyama, T, Wei, L, Nakayama, A, Nakamura, T, Sakiyama, M, Takada, T, Taketani, Y, Suma, S, Naito, M, Oda, T, Kumagai, H, Moriyama, Y, Ichida, K, Shimizu, T, Kanai, Y & Shinomiya, N 2015, 'NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout', Arthritis and Rheumatology, vol. 67, no. 1, pp. 281-287. https://doi.org/10.1002/art.38884
Chiba, Toshinori ; Matsuo, Hirotaka ; Kawamura, Yusuke ; Nagamori, Shushi ; Nishiyama, Takashi ; Wei, Ling ; Nakayama, Akiyoshi ; Nakamura, Takahiro ; Sakiyama, Masayuki ; Takada, Tappei ; Taketani, Yutaka ; Suma, Shino ; Naito, Mariko ; Oda, Takashi ; Kumagai, Hiroo ; Moriyama, Yoshinori ; Ichida, Kimiyoshi ; Shimizu, Toru ; Kanai, Yoshikatsu ; Shinomiya, Nariyoshi. / NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 1. pp. 281-287.
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abstract = "Objective Serum uric acid (SUA) levels in humans are mainly regulated by urate transporters. Recent genome-wide association studies suggested that common variants of the human sodium-dependent phosphate cotransporter type 1 gene (NPT1/SLC17A1) influence SUA. NPT1 has been reported to mediate urate transport, but its physiologic role in regulating SUA in humans remains unclear. Furthermore, the findings of replication studies of the relationship between NPT1 variants and gout have been inconsistent. The aims of this study were to investigate the effect of NPT1 on gout and to determine its physiologic role.Methods Five hundred forty-five male Japanese patients with gout and 1,115 male Japanese control subjects were genotyped for rs1165196 (I269T), a common missense variant in NPT1. Analyses of the association between rs1165196 and gout were then conducted, focusing especially on renal underexcretion (RUE) gout. Immunohistochemical analysis and functional analysis using Xenopus oocytes were also performed.Results Single-nucleotide polymorphism rs1165196 significantly decreased the risk of RUE gout (odds ratio 0.73, P = 0.031) but did not confer a risk for all gout (P = 0.123). The immunohistochemical analysis revealed that human NPT1 is localized to the apical membrane of the renal proximal tubule. The functional analysis using Xenopus oocyte expression systems showed that rs1165196 increases NPT1-mediated urate export.Conclusion This study showed that NPT1 is a urate exporter located in the renal proximal tubule in humans, and that its common gain-of-function variant, rs1165196, causes RUE gout, a major subtype of gout. These findings enable us to deepen our understanding of the physiologic role of NPT1 as a renal urate exporter as well as its pathophysiologic role in gout.",
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T1 - NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout

AU - Chiba, Toshinori

AU - Matsuo, Hirotaka

AU - Kawamura, Yusuke

AU - Nagamori, Shushi

AU - Nishiyama, Takashi

AU - Wei, Ling

AU - Nakayama, Akiyoshi

AU - Nakamura, Takahiro

AU - Sakiyama, Masayuki

AU - Takada, Tappei

AU - Taketani, Yutaka

AU - Suma, Shino

AU - Naito, Mariko

AU - Oda, Takashi

AU - Kumagai, Hiroo

AU - Moriyama, Yoshinori

AU - Ichida, Kimiyoshi

AU - Shimizu, Toru

AU - Kanai, Yoshikatsu

AU - Shinomiya, Nariyoshi

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N2 - Objective Serum uric acid (SUA) levels in humans are mainly regulated by urate transporters. Recent genome-wide association studies suggested that common variants of the human sodium-dependent phosphate cotransporter type 1 gene (NPT1/SLC17A1) influence SUA. NPT1 has been reported to mediate urate transport, but its physiologic role in regulating SUA in humans remains unclear. Furthermore, the findings of replication studies of the relationship between NPT1 variants and gout have been inconsistent. The aims of this study were to investigate the effect of NPT1 on gout and to determine its physiologic role.Methods Five hundred forty-five male Japanese patients with gout and 1,115 male Japanese control subjects were genotyped for rs1165196 (I269T), a common missense variant in NPT1. Analyses of the association between rs1165196 and gout were then conducted, focusing especially on renal underexcretion (RUE) gout. Immunohistochemical analysis and functional analysis using Xenopus oocytes were also performed.Results Single-nucleotide polymorphism rs1165196 significantly decreased the risk of RUE gout (odds ratio 0.73, P = 0.031) but did not confer a risk for all gout (P = 0.123). The immunohistochemical analysis revealed that human NPT1 is localized to the apical membrane of the renal proximal tubule. The functional analysis using Xenopus oocyte expression systems showed that rs1165196 increases NPT1-mediated urate export.Conclusion This study showed that NPT1 is a urate exporter located in the renal proximal tubule in humans, and that its common gain-of-function variant, rs1165196, causes RUE gout, a major subtype of gout. These findings enable us to deepen our understanding of the physiologic role of NPT1 as a renal urate exporter as well as its pathophysiologic role in gout.

AB - Objective Serum uric acid (SUA) levels in humans are mainly regulated by urate transporters. Recent genome-wide association studies suggested that common variants of the human sodium-dependent phosphate cotransporter type 1 gene (NPT1/SLC17A1) influence SUA. NPT1 has been reported to mediate urate transport, but its physiologic role in regulating SUA in humans remains unclear. Furthermore, the findings of replication studies of the relationship between NPT1 variants and gout have been inconsistent. The aims of this study were to investigate the effect of NPT1 on gout and to determine its physiologic role.Methods Five hundred forty-five male Japanese patients with gout and 1,115 male Japanese control subjects were genotyped for rs1165196 (I269T), a common missense variant in NPT1. Analyses of the association between rs1165196 and gout were then conducted, focusing especially on renal underexcretion (RUE) gout. Immunohistochemical analysis and functional analysis using Xenopus oocytes were also performed.Results Single-nucleotide polymorphism rs1165196 significantly decreased the risk of RUE gout (odds ratio 0.73, P = 0.031) but did not confer a risk for all gout (P = 0.123). The immunohistochemical analysis revealed that human NPT1 is localized to the apical membrane of the renal proximal tubule. The functional analysis using Xenopus oocyte expression systems showed that rs1165196 increases NPT1-mediated urate export.Conclusion This study showed that NPT1 is a urate exporter located in the renal proximal tubule in humans, and that its common gain-of-function variant, rs1165196, causes RUE gout, a major subtype of gout. These findings enable us to deepen our understanding of the physiologic role of NPT1 as a renal urate exporter as well as its pathophysiologic role in gout.

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