Recent insights into the pathogenesis of hyperuricaemia and gout

Human Molecular Genetics, Oct 2009

Gout is a common rheumatic disease in humans which is characterized by elevation in serum uric acid levels, and deposition of uric acid crystals in the joint. Hyperuricaemia is the primary risk factor for the development of gout and primates have uniquely high levels of serum uric acid due to missense mutations in the uricase gene. Levels of serum uric acid are known to be highly heritable, and mutations in genes which encode enzymes in the purine salvage pathway have long been recognized as rare causes of gout. Until recently, however, little has been known about the genetic determinants of urate metabolism and susceptibility to gout in the general population. Over recent months, a series of large scale genome wide association studies have been performed which have shed new light on the genes which regulate serum uric acid levels and susceptibility to gout. Most of these genes seem to be involved in regulating the renal excretion of uric acid which underscores the importance of reduced urate excretion as opposed to increased endogenous production as a cause of gout. Further work will now be required to investigate the mechanisms by which these genetic variants regulate urate excretion and serum urate levels. However, it seems likely that the genes so far identified will represent new molecular targets for the design of drugs to enhance urate excretion and the genetic variants that predispose to gout might be of value as genetic markers of susceptibility to gout.

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Recent insights into the pathogenesis of hyperuricaemia and gout

Philip L. Riches 1 Alan F. Wright 0 Stuart H. Ralston 1 0 MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh , Edinburgh EH4 2XU , UK 1 Rheumatic Diseases Unit Gout is a common rheumatic disease in humans which is characterized by elevation in serum uric acid levels, and deposition of uric acid crystals in the joint. Hyperuricaemia is the primary risk factor for the development of gout and primates have uniquely high levels of serum uric acid due to missense mutations in the uricase gene. Levels of serum uric acid are known to be highly heritable, and mutations in genes which encode enzymes in the purine salvage pathway have long been recognized as rare causes of gout. Until recently, however, little has been known about the genetic determinants of urate metabolism and susceptibility to gout in the general population. Over recent months, a series of large scale genome wide association studies have been performed which have shed new light on the genes which regulate serum uric acid levels and susceptibility to gout. Most of these genes seem to be involved in regulating the renal excretion of uric acid which underscores the importance of reduced urate excretion as opposed to increased endogenous production as a cause of gout. Further work will now be required to investigate the mechanisms by which these genetic variants regulate urate excretion and serum urate levels. However, it seems likely that the genes so far identified will represent new molecular targets for the design of drugs to enhance urate excretion and the genetic variants that predispose to gout might be of value as genetic markers of susceptibility to gout. - INTRODUCTION Gout is a common rheumatic disease in humans which is characterized by elevation in serum uric acid levels, deposition of uric acid crystals in the joint and an acute inflammatory arthritis (1). The prevalence of gout in both UK and German populations has been reported as 1.4% (2,3) making it the commonest cause of inflammatory arthritis in men. Hyperuricaemia is the most important risk factor for the development of gout with the likelihood of developing gout rising exponentially in line with serum urate levels (4). Despite this strong association the majority of patients with hyperuricaemia do not develop gout; the annual incidence of gout is estimated to be only 5% in patients with levels of serum urate above 9 mg/dl (4,5). Serum levels of urate follow a normal distribution in the general population but levels are higher in men, which probably accounts for the fact that clinical gout is about five times more common in men than in women. Although genetic factors play an important role in regulating serum urate levels, these can also be influenced by increased intake of purines or other factors such as fructose which influence urate metabolism (Fig. 1). Humans have uniquely high basal levels of serum uric acid due to three separate missense mutations resulting in a non-functioning uricase gene (6,7). In an analysis of four hominoid species the human mutations of urate oxidase were identified in chimpanzees and orang utang but an independent deletion event was found in gibbons suggesting that survival advantage accrued from loss of urate oxidase (6). Genetic factors play an important role in the pathogenesis of gout and regulation of serum uric acid levels. Twin studies have shown that the renal handling of uric acid is strongly heritable (8). This is of relevance to the pathogenesis of gout since, for more than 90% of patients, the primary problem is reduced renal excretion of uric acid (1). Segregation analysis in families has shown that serum uric acid levels also have a significant heritable component (heritability 0.4) with an overall pattern of inheritance that is consistent with a complex trait, regulated by an interaction between more than one major gene, several modifying genes and environmental factors (9). SINGLE GENE DISORDERS THAT CAUSE HYPERURICAEMIA AND GOUT Gout and hyperuricaemia can occasionally be inherited in a Mendelian manner (Table 1). For example, inactivation mutations in hypoxanthine-guanine phosphoribosyl transferase (HGPRT)a gene involved in the purine salvage pathway can cause hyperuricaemia and gout in the form of Lesch Nyhan syndrome (10). This is an X-linked recessive disorder which varies in severity depending on the type of mutation and its effect on catalytic activity of HGPRT. Another Mendelian form of gout occurs in patients with activating mutations in phosphoribosyl pyrophosphatase synthetase (11) an enzyme that is involve in urate synthesis. This causes X-linked dominant inheritance of primary hyperuricaemia and gout. Gout and hyperuricaemia can also occur in patients with glycogen storage diseases (12) and some other rare inborn errors of metabolism (Table 1). Autosomal dominant syndromes of hyperuricaemic nephropathy associated with reduced fractional excretion of uric acid have been (...truncated)


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Philip L. Riches, Alan F. Wright, Stuart H. Ralston. Recent insights into the pathogenesis of hyperuricaemia and gout, Human Molecular Genetics, 2009, pp. R177-R184, 18/R2, DOI: 10.1093/hmg/ddp369