Mendelian randomization analysis associates increased serum urate, due to genetic variation in uric acid transporters, with improved renal function

Kidney Int. 2014 Feb;85(2):344-51. doi: 10.1038/ki.2013.353. Epub 2013 Sep 18.

Abstract

Increased serum urate predicts chronic kidney disease independent of other risk factors. The use of xanthine oxidase inhibitors coincides with improved renal function. Whether this is due to reduced serum urate or reduced production of oxidants by xanthine oxidase or another physiological mechanism remains unresolved. Here we applied Mendelian randomization, a statistical genetics approach allowing disentangling of cause and effect in the presence of potential confounding, to determine whether lowering of serum urate by genetic modulation of renal excretion benefits renal function using data from 7979 patients of the Atherosclerosis Risk in Communities and Framingham Heart studies. Mendelian randomization by the two-stage least squares method was done with serum urate as the exposure, a uric acid transporter genetic risk score as instrumental variable, and estimated glomerular filtration rate and serum creatinine as the outcomes. Increased genetic risk score was associated with significantly improved renal function in men but not in women. Analysis of individual genetic variants showed the effect size associated with serum urate did not correlate with that associated with renal function in the Mendelian randomization model. This is consistent with the possibility that the physiological action of these genetic variants in raising serum urate correlates directly with improved renal function. Further studies are required to understand the mechanism of the potential renal function protection mediated by xanthine oxidase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers / blood
  • Confounding Factors, Epidemiologic
  • Creatinine / blood
  • Enzyme Inhibitors / therapeutic use
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Predisposition to Disease
  • Glomerular Filtration Rate
  • Humans
  • Kidney / drug effects
  • Kidney / enzymology
  • Kidney / physiopathology*
  • Least-Squares Analysis
  • Linear Models
  • Male
  • Mendelian Randomization Analysis*
  • Models, Genetic
  • Models, Statistical
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Principal Component Analysis
  • Recovery of Function
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / enzymology
  • Renal Insufficiency, Chronic / ethnology
  • Renal Insufficiency, Chronic / genetics*
  • Renal Insufficiency, Chronic / physiopathology
  • Risk Factors
  • Treatment Outcome
  • United States / epidemiology
  • Up-Regulation
  • Uric Acid / blood*
  • Xanthine Oxidase / antagonists & inhibitors
  • Xanthine Oxidase / metabolism

Substances

  • Biomarkers
  • Enzyme Inhibitors
  • Organic Anion Transporters
  • Uric Acid
  • Creatinine
  • Xanthine Oxidase