ReviewThe genetic basis of hyperuricaemia and gout
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.
References (60)
- et al.
Studies on the mechanism of fructose-induced hyperuricemia in man
Metabolism
(1972) - et al.
Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia
Am J Hum Genet
(2008) - et al.
Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide study
Lancet
(2008) - et al.
Identification and characterization of human glucose transporter-like protein-9 (GLUT9): alternative splicing alters trafficking
J Biol Chem
(2004) - et al.
Gout
Lancet
(2010) - et al.
Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene
Kidney Int
(2003) - et al.
Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and chronic kidney failure
Am J Hum Genet
(2009) - et al.
Human X-linked phosphoribosylpyrophosphate synthetase superactivity is associated with distinct point mutations in the PRPS1 gene
J Biol Chem
(1993) - et al.
Two independent mutational events in the loss of urate oxidase during hominoid evolution
J Mol Evol
(1992) - et al.
Mechanisms of bone erosion in gout: a quantitative analysis using plain radiography and computed tomography
Ann Rheum Dis
(2009)
Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study
Br Med J
Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey
Arthritis Rheum
Hyperuricaemia, gout and kidney function in New Zealand Maori men
Br J Rheumatol
Polynesian women are also at risk for hyperuricaemia and gout because of a genetic defect in renal urate handling
Br J Rheumatol
Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout
Rheumatology (Oxford)
SLC2A9 is a high-capacity urate transporter in humans
PLoS Med
Molecular identification of a renal urate anion exchanger that regulates blood urate levels
Nature
Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout
Proc Natl Acad Sci U S A
SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout
Nat Genet
Human renal organic anion transporter 4 operates as an asymmetric urate transporter
J Am Soc Nephrol
Monosodium urate crystals in the knee joints of patients with asymptomatic nontophaceous gout
Arthritis Rheum
A role of IgM antibodies in monosodium urate crystal formation and associated adjuvanticity
J Immunol
Gout-associated uric acid crystals activate the NALP3 inflammasome
Nature
The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis
Nat Immunol
Mechanisms of inflammation in gout
Rheumatology (Oxford)
The human genome and understanding of human disease: present and future technologies
Cell Mol Life Sci
The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts
PLoS Genet
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects
Nat Genet
Association of a common nonsynonymous variant in GLUT9 with serum uric acid levels in old order Amish
Arthritis Rheum
Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study
PLoS ONE
Cited by (138)
A biosensing array for multiplex clinical evaluation of glucose, creatinine, and uric acid
2023, Biosensors and BioelectronicsProgress in optical sensors-based uric acid detection
2023, Biosensors and BioelectronicsThe Effects of Gout Following total Knee Arthroplasty: A Retrospective Analysis
2023, Journal of Arthroplasty