title: Association of four genetic loci with uric acid levels and reduced renal function: the J-SHIPP Suita study.
abstract: BACKGROUND
  Recent genome-wide association studies have identified several genetic variants as susceptibility loci for serum uric acid (UA) levels. We also identified a common nonsense mutation, W258X, responsible for renal hypouricemia. Here, we investigated clinical implications of these genetic variants by cross-sectional and longitudinal genetic epidemiological analysis.
  
  
  METHODS
  The study enrolled 5,165 Japanese subjects aged 64 ± 12 years from the general population. Clinical parameters were obtained from the personal health records, evaluated at medical checkups.
  
  
  RESULTS
  Serum UA levels were significantly different between the SLC22A12 rs11231825 (CC/CT/TT: 4.5 ± 1.6, 5.0 ± 1.4, 5.3 ± 1.4 mg/dl; p = 7.6 × 10(-20)), SLC2A9 rs1014290 (TT/TG/GG: 4.9 ± 1.4, 5.1 ± 1.4, 5.3 ± 1.4 mg/dl; p = 3.1 × 10(-11)) and ABCG2 rs2231142 (TT/TG/GG: 5.3 ± 1.5, 5.2 ± 1.4, 5.1 ± 1.4 mg/dl; p = 2.0 × 10(-5)) genotypes. During 9.4 years of follow-up, 87 new cases of hyperuricemia were diagnosed. Multiple logistic regression analysis identified the accumulation of risk alleles as a significant determinant of future development of hyperuricemia (OR = 7.94; 95% CI: 1.97-53.6). In contrast, subjects with nonsense mutation predominantly showed lower UA levels (XX/XW/WW: 1.3 ± 1.7, 3.6 ± 1.0, 5.2 ± 1.4 mg/dl; p = 9.3 × 10(-82)). However, these subjects showed significantly reduced renal function (β = -0.111; p < 0.001) independently of possible covariates.
  
  
  CONCLUSIONS
  Accumulation of risk genotypes was an independent risk factor for future development of hyperuricemia. Genetically developed hypouricemia was an independent risk factor for decreased renal function.
authors: Yasuharu
authors: Y
authors: Tabara
authors: Katsuhiko
authors: K
authors: Kohara
authors: Ryuichi
authors: R
authors: Kawamoto
authors: Yumiko
authors: Y
authors: Hiura
authors: Kunihiro
authors: K
authors: Nishimura
authors: Takayuki
authors: T
authors: Morisaki
authors: Yoshihiro
authors: Y
authors: Kokubo
authors: Tomonori
authors: T
authors: Okamura
authors: Hitonobu
authors: H
authors: Tomoike
authors: Naoharu
authors: N
authors: Iwai
authors: Tetsuro
authors: T
authors: Miki
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D044466:Asian People / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D005919:Glomerular Filtration Rate / Q000235:genetics*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006073:Gout / Q000209:etiology; D006801:Humans; D033461:Hyperuricemia / Q000453:epidemiology / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D014527:Uric Acid / Q000097:blood*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D051246:Glucose Transport Proteins, Facilitative; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D014527:Uric Acid