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An update on the genetics of hyperuricaemia and gout

Abstract

A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.

Key points

  • The progression to clinically evident gout is thought to occur via several phases — from hyperuricaemia to the deposition of monosodium urate crystals to clinical gout that results from an innate immune response to these crystals.

  • Genome-wide association studies reveal that the genetic basis of hyperuricaemia is dominated by loci containing urate transporters involved in the excretion of urate by the kidneys and the gut.

  • The genetic basis of progression to clinical gout is not well understood, although candidate gene studies have detected association of genes encoding proteins that influence the activation and activity of the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome with gout; future research should focus on large genome-wide association studies in gout, including using control asymptomatic individuals with hyperuricaemia.

  • Genome-wide and targeted sequencing data reveal uncommon, population-specific and penetrant genetic variants that provide relatively immediate insights into the pathogenesis of hyperuricaemia and gout and opportunities for clinical translation.

  • Genetic variants that predict the response of individuals with hyperuricaemia to urate-lowering drugs are being identified.

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Fig. 1: Development of hyperuricaemia and progression to gout.
Fig. 2: Genome-wide plot summarizing data from genome-wide association studies of serum urate levels.
Fig. 3: Tissue-focused functional heritability enrichments.
Fig. 4: Genome-wide plot summarizing data from genome-wide, replication and candidate gene association studies of gout.

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Acknowledgements

The authors thank the Health Research Council of New Zealand and the University of Otago, Dunedin, New Zealand, for salary funding for T.J.M. and T.R.M.

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Nature Reviews Rheumatology thanks K. Pavelka and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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T.J.M., N.D. and T.R.M. contributed to researching data for the article; N.D., E.A.S. and T.R.M. contributed to discussion of content; N.D. and T.R.M. contributed to writing the article; and T.J.M., N.D. and E.A.S. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Tony R. Merriman.

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Competing interests

N.D. declares that she has received consulting fees, speaker fees or grants from Ardea/AstraZeneca, Cymabay, Crealta, Horizon and Takeda, which have developed or marketed urate-lowering therapies for management of gout. T.R.M. declares that he has received consulting fees, speaker fees or grants from Ardea/AstraZeneca and Horizon, which have developed or marketed urate-lowering therapies for management of gout. The other authors declare no competing interests.

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41584_2018_4_MOESM1_ESM.pdf

Supplementary Figure S1 Genetic epidemiological (Mendelian randomization) evidence that serum urate is not causal for comorbidities associated with gout

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Major, T.J., Dalbeth, N., Stahl, E.A. et al. An update on the genetics of hyperuricaemia and gout. Nat Rev Rheumatol 14, 341–353 (2018). https://doi.org/10.1038/s41584-018-0004-x

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