title: NPT1/SLC17A1 is a renal urate exporter in humans and its common gain-of-function variant decreases the risk of renal underexcretion gout.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Defense Medical College, Tokorozawa, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Chiba
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishiyama
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Taketani
authors.forename: Shino
authors.initials: S
authors.lastname: Suma
authors.forename: Mariko
authors.initials: M
authors.lastname: Naito
authors.forename: Takashi
authors.initials: T
authors.lastname: Oda
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Moriyama
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.forename: Toru
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006073:Gout / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009865:Oocytes / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D050609:Sodium-Phosphate Cotransporter Proteins, Type I / Q000235:genetics* / Q000502:physiology*; D014527:Uric Acid / Q000378:metabolism*; D014981:Xenopus
chemical_list: C493546:SLC17A1 protein, human; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D014527:Uric Acid