title: Mendelian randomization of serum urate and parkinson disease progression.
abstract: OBJECTIVE
  Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach.
  
  
  METHODS
  The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment.
  
  
  RESULTS
  Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression.
  
  
  CONCLUSIONS
  This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Kelly Claire
authors.initials: KC
authors.lastname: Simon
authors.forename: Shirley
authors.initials: S
authors.lastname: Eberly
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Oakes
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Tanner
authors.forename: Ira
authors.initials: I
authors.lastname: Shoulson
authors.forename: Stanley
authors.initials: S
authors.lastname: Fahn
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schwarzschild
authors.forename: Alberto
authors.initials: A
authors.lastname: Ascherio
mesh_terms: D015415:Biomarkers / Q000097:blood; D018450:Disease Progression; D005500:Follow-Up Studies; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics*; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods*; D010300:Parkinson Disease / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014527:Uric Acid / Q000097:blood*
chemical_list: D015415:Biomarkers; D051246:Glucose Transport Proteins, Facilitative; C411811:SLC2A9 protein, human; D014527:Uric Acid