Molecular Genetics of Hyperuricaemia and Gout

Abstract

Gout results from an innate immune reaction to monosodium urate crystals deposited in the joints of individuals with elevated serum urate levels (hyperuricaemia). Urate, the primary cause of gout, is a metabolite with beneficial properties. The use of genome‐wide association scanning has identified 28 loci that control serum urate levels. Predominant among these are loci containing uric acid transporter genes involved in renal and gut excretion of uric acid. The SLC2A9 (GLUT9) and ABCG2 genes have particularly strong effects on serum urate and risk of gout. In contrast to serum urate, the genetic control of inflammatory gout is very poorly understood, largely because no genome‐wide association scan has been conducted using clinically ascertained gout cases. Similarly, the full‐scope of the beneficial (or harmful) properties of urate is currently unknown; a genetic technique called Mendelian randomisation is being employed to better understand the relationship between urate and other metabolic conditions.

Key Concepts:

  • Urate is evolutionarily beneficial.

  • Urate is under genetic control.

  • Genetic variants in genes involved in the excretion of uric acid have the strongest effect on serum urate.

  • A total of 28 loci have been associated with control of serum urate.

  • Not all genes associated with serum urate have been associated with gout.

  • There are no genes associated with inflammatory gout with robust statistical evidence.

Keywords: urate; gout; gene; association; single‐nucleotide polymorphism; genome‐wide association study; SLC2A9; ABCG2; mendelian randomisation

Figure 1.

Current knowledge of urate transporters within the apical membrane of the kidney proximal tubule. Transporters are labelled using their protein names, those mentioned in the text under their gene names are: SLC2A9 (two isoforms SLC2A9a (GLUT9L), SLC2A9b (GLUT9S)), SLC17A1 (NPT1), SLC22A11 (OAT4), SLC22A12 (URAT1) and SLC22A7 (OAT2).

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Further reading

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Merriman, Tony R, and Flynn, Tanya J(Oct 2013) Molecular Genetics of Hyperuricaemia and Gout. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025153]