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.

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control

“…The loci of strongest effect are dominated by renal and gut transporters of urate, with two loci ( SLC2A9 and ABCG2 ) together explaining up to 5% of variance in serum urate levels in Europeans [4]. Most of these 36 loci also associate with gout in multiple ancestral groups [4, 7–9]. There has, however, been little progress on understanding the molecular basis of the association for the various loci.…”

Management of gout in older people

“…Conversely, individuals with urate concentrations <0.42 mmol/L can present with gout. We now know that the propensity to experience gout attacks is affected by an individual's innate immunity and ability to trigger the formation of the ‘inflammasome’ in response to crystals of urate forming in joints . One complication in evaluating suspected gout is that the serum urate concentration drops during an acute attack, which may divert the clinician from consideration of the diagnosis.…”

“…We now know that the propensity to experience gout attacks is affected by an individual's innate immunity and ability to trigger the formation of the 'inflammasome' in response to crystals of urate forming in joints. 24,25 One complication in evaluating suspected gout is that the serum urate concentration drops during an acute attack, which may divert the clinician from consideration of the diagnosis. A definitive diagnosis is made by demonstrating needle-shaped, negatively birefringent crystals in aspirated joint fluid.…”

Pleiotropic effect of ABCG2 in gout: involvement in serum urate levels and progression from hyperuricemia to gout

“…The pathway that produces IL-1β involves activation of the NLRP3 inflammasome, resulting in cleavage of pro-IL-1β to mature IL-1β by caspase-1. There is little knowledge, however, about the genetic variants that promote the formation of MSU crystals and initiate the innate immune response in the presence of HU (9), although variants in the toll-like receptor 4 and components of the NLRP3 inflammasome have been associated with increased risk of gout (10-12).…”