title: Association of a polymorphism in a gene encoding a urate transporter with CKD progression.
abstract: OBJECTIVE
  Hyperuricemia predicts a high risk for CKD progression but there is no large clinical trial in humans indicating that this relationship is causal in nature. The rs734553 single-nucleotide polymorphism (SNP) of the GLUT9 urate transporter gene was strongly associated with uric acid (UA) levels in a large meta-analysis.
  
  
  METHODS
  This prospective study adopted the Mendelian randomization approach. The rs734553 SNP was used as an instrumental variable to investigate the relationship between UA and renal outcomes in a cohort of 755 patients with CKD who were enrolled between October 18, 2005, and October 2, 2008. The association between the polymorphism and UA was preliminary confirmed in a series of 211 healthy volunteers enrolled between January 1, 2001, and July 12, 2011, from the same geographic area as the patients with CKD. The study end point was a composite renal-end point (i.e., >30% decrease in the GFR, dialysis, or transplantation). Patients were followed up for a median of 36 months.
  
  
  RESULTS
  In healthy individuals, serum UA levels were highest in homozygotes for the T allele (risk allele), intermediate in heterozygotes for the same allele, and lowest in those without the risk allele (P<0.001), but no such relationship was found in patients with CKD. In the CKD cohort, homozygotes (TT) and heterozygotes (GT) for the risk allele had a 2.35 times higher risk (hazard ratio, 2.35; 95% confidence interval, 1.25 to 4.42; P=0.008) of CKD progression. The risk for CKD progression by rs734553 remained unmodified in analyses adjusting for proteinuria, GFR, and other classical and CKD-peculiar risk factors.
  
  
  CONCLUSIONS
  A GLUT9 polymorphism, which is strongly associated with serum UA levels in healthy individuals of the general population with normal renal function, holds a strong predictive power for CKD progression. These findings are compatible with the hypothesis that the link between UA and CKD progression is causal in nature.
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Testa
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Mallamaci
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Belinda
authors.initials: B
authors.lastname: Spoto
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pisano
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sanguedolce
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tripepi
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Leonardis
authors.affiliation: Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, National Research Council, Institute of Biomedicine and Molecular Biology, Reggio, Calabria, Italy carmine.zoccali@tin.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Zoccali
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011507:Proteinuria / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000503:physiopathology; D014527:Uric Acid / Q000097:blood; D055815:Young Adult
chemical_list: D051246:Glucose Transport Proteins, Facilitative; C411811:SLC2A9 protein, human; D014527:Uric Acid
keywords: CKD progression; epidemiology; polymorphisms; uric acid
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