The genetics of hyperuricaemia and gout

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Gout is a common and very painful inflammatory arthritis caused by hyperuricaemia. This Review provides an update on the genetics of hyperuricaemia and gout, including findings from genome-wide association studies. Most of the genes that associated with serum uric acid levels or gout are involved in the renal urate-transport system. For example, the urate transporter genes SLC2A9, ABCG2 and SLC22A12 modulate serum uric acid levels and gout risk. The net balance between renal urate absorption and secretion is a major determinant of serum uric acid concentration and loss-of-function mutations in SLC2A9 and SLC22A12 cause hereditary hypouricaemia due to reduced urate absorption and unopposed urate secretion. However, the variance in serum uric acid explained by genetic variants is small and their clinical utility for gout risk prediction seems limited because serum uric acid levels effectively predict gout risk. Urate-associated genes and genetically determined serum uric acid levels were largely unassociated with cardiovascular–metabolic outcomes, challenging the hypothesis of a causal role of serum uric acid in the development of cardiovascular disease. Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions were shown in Asian and European populations. Genetic testing for HLA-B*5801 alleles could be used to predict these potentially fatal adverse effects.

Key Points

  • The majority of the genes that associate with hyperuricaemia and gout in genome-wide association studies have been implicated in the renal urate-transport system

  • Genetic variation explains only a modest level of variance in serum uric acid levels (6%)

  • Serum uric acid levels are determined by the net balance between urate absorption and secretion, which is mediated by separate sets of transporters in the renal proximal tubule

  • The clinical utility of testing for urate-associated genes seems limited because serum urate levels themselves can effectively predict gout risk at a low cost

  • Urate-associated genes and genetically determined urate levels have been largely unassociated with cardiovascular or metabolic outcomes, suggesting that serum uric acid does not have a causal role in these outcomes

  • Strong pharmacogenetic associations between HLA-B*5801 alleles and severe allopurinol-hypersensitivity reactions have been shown in Asian and European populations, suggesting clinical utility of testing for these alleles

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Figure 1: Genetic variants implicated in the pathogenesis of hyperuricaemia or gout.
Figure 2: The uric acid transportasome.
Figure 3: The pathogenesis of hyperuricaemia and gout.


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This work was partly supported by grants from the NIH (R01AR056291 and P60AR047785).

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All authors contributed equally to researching the data for the article, discussions of the content, writing the article and editing of the manuscript before submission.

Correspondence to Hyon K. Choi.

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A. M. Reginato is a consultant for URL and a member of the speakers bureau (honoraria) for Savient, Takeda and URL. D B. Mount has received grant or research support from Nuon and URL. H. K. Choi has received grant or research support from Takeda and URL. I. Yang declares no competing interests.

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