Elsevier

Joint Bone Spine

Volume 78, Issue 1, January 2011, Pages 35-40
Joint Bone Spine

Review
The genetic basis of hyperuricaemia and gout

https://doi.org/10.1016/j.jbspin.2010.02.027Get rights and content

Abstract

Gout results from elevated urate concentrations in the blood (hyperuricaemia). When super-saturation of urate is reached, monosodium urate crystals form within the joint. In some individuals, these crystals elicit a painful self-limiting inflammatory response that is characteristic of acute gouty arthritis. The most important cause of hyperuricaemia is reduced excretion of uric acid in the urine. Uric acid excretion is coordinated by a suite of urate transport molecules expressed in the renal collecting tubules, and is a key physiological checkpoint in gout. Other checkpoints in gout are hepatic production of urate, monosodium urate crystal formation, and initiation of the acute inflammatory response. Genome-wide association scans for genes regulating serum urate concentrations have identified two major regulators of hyperuricaemia– the renal urate transporters SLC2A9 and ABCG2. The risk variants at each gene approximately double the risk for gout in people of Caucasian ancestry, with SLC2A9 also resulting in higher risk for gout in people of Polynesian ancestry, a diverse population characterized by a high prevalence of gout. Ongoing genetic association studies are identifying and confirming other genes controlling serum urate concentrations; although genome-wide association studies in gout per se await recruitment of suitable case sample sets.

Introduction

Gout is the most common form of inflammatory arthritis affecting men, occurring in 1-2% of Caucasian men in Westernized countries. The central biochemical cause of gout is excess urate. In most mammals urate is degraded by uricase to allantoin, which is highly soluble and readily excreted in the urine. During the Miocene period, two parallel mutations occurred in early hominids that disabled the uricase gene, resulting in higher serum urate concentrations [1]. The parallel mutations suggest that inactivating the uricase gene was selectively advantageous to early hominids, possibly due to one, or a combination, of: the anti-oxidant activity of uric acid compensating for vitamin C deficiency; the ability of uric acid to maintain blood pressure under low-salt dietary conditions; the adjuvant activity of uric acid. Hyperuricaemia is the key predictor for development of gout – elevated urate above super-saturation concentrations [6.8 mg/dL at physiological pH and temperature] leads to the formation of monosodium urate (MSU) crystals within joints and subcutaneous tissues with the development of very painful attacks of gouty arthritis. Early gouty arthritis is characterized by recurrent episodes of self-limiting acute inflammatory attacks of monoarthritis. Subsequently, gout progresses with more frequent attacks that involve multiple joints. In some patients, chronic tophaceous disease may develop with progressive joint destruction and disability [2].

Section snippets

Urate production

Urate is a product of hepatic purine metabolism, produced through metabolism of ingested purines (de novo synthesis) and endogenous metabolism of purines (salvage pathways). Hyperuricaemia may occur as a result of urate over-production, due to acquired causes such as high purine diet, fructose ingestion, alcohol intake, and myeloproliferative disorders, and also rare genetic causes such as hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and PRPP synthetase (PRS) superactivity.

The genetic basis for hyperuricaemia and gout

The previous two years have seen considerable inroads into the understanding of the genetic basis of hyperuricaemia and gout (Table 1). The Human Genome Project, large population-based cohorts and technologies enabling massively parallel assessment of genomic variation have enabled genome-wide association scanning [19]. This advance in knowledge has come from genome-wide association scans (GWAS) examining genetic factors controlling serum urate concentrations, a simple phenotype to measure, yet

Gout in Polynesia

Although the prevalence of gout is increasing worldwide [47], certain populations have higher rates of gout. Possible gouty erosions in skeletons from the 3000-year old Polynesian Lapita culture in Vanuatu have been reported [48]. Lesions consistent with gout were present in seven out of 20 skeletons (all male). The incidence of gout is 2% in men living on Tokelau, rising to 5% upon migration to New Zealand [49]. Both Tokelau cohorts had mean urate concentrations in the hyperuricaemic range. On

Conclusion

Major advances in the understanding of the genetic basis of hyperuricaemia have occurred in the last two years. These findings have primarily focused on renal excretion of uric acid. In particular, the importance of SLC2A9 has been consistently demonstrated, highlighting the potential role of this transporter as a novel drug target. However, it should be noted that genetic variation in SLC2A9 explains only ∼5% of the total variation of serum urate concentrations in people of Caucasian ancestry,

Conflict of interest

Neither of the authors has any conflicts of interest to declare.

Acknowledgement

The authors would like to thank Bronwyn Carlisle for her expert help in Fig. 1, Fig. 2.

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