Abstract
The pathogenesis of gout involves a series of steps beginning with hyperuricaemia, followed by the deposition of monosodium urate crystal in articular structures and culminating in an innate immune response, mediated by the NLRP3 inflammasome, to the deposited crystals. Large genome-wide association studies (GWAS) of serum urate levels initially identified the genetic variants with the strongest effects, mapping mainly to genes that encode urate transporters in the kidney and gut. Other GWAS highlighted the importance of uncommon genetic variants. More recently, genetic and epigenetic genome-wide studies have revealed new pathways in the inflammatory process of gout, including genetic associations with epigenomic modifiers. Epigenome-wide association studies are also implicating epigenomic remodelling in gout, which perhaps regulates the responsiveness of the innate immune system to monosodium urate crystals. Notably, genes implicated in gout GWAS do not include those encoding components of the NLRP3 inflammasome itself, but instead include genes encoding molecules involved in its regulation. Knowledge of the molecular mechanisms underlying gout has advanced through the translation of genetic associations into specific molecular mechanisms. Notable examples include ABCG2, HNF4A, PDZK1, MAF and IL37. Current genetic studies are dominated by participants of European ancestry; however, studies focusing on other population groups are discovering informative population-specific variants associated with gout.
Genetic, epigenetic and transcriptomic studies in hyperuricaemia and gout have, in the past 6 years, provided important insights into the underlying molecular mechanisms, revealing new inflammatory pathways and epigenetic factors and expanding research beyond European populations.
Genome-wide association studies (GWAS) of serum urate levels show that common genetic variants within loci encoding urate transporters and ancillary molecules confer the strongest genetic effects on the risk of hyperuricaemia and gout.Exome-wide analyses of urate levels show that uncommon protein-coding variants in established hyperuricaemia risk genes exert strong effects, emphasizing the valuable translational insights gained from identifying uncommon risk variants.Epigenome-wide analyses of urate levels highlight DNA methylation of and of genes encoding molecules involved in amino acid transport and metabolism as key factors in the epigenetic regulation of urate homeostasis.Genome-wide association studies of gout highlight the importance of epigenomic pathways, suggesting that epigenetic reprogramming of innate immune cells by soluble urate increases their responsiveness to monosodium urate crystals.Genome-wide association studies of gout are yet to be conducted in under-represented populations; however, the identification of population-specific genetic variants is providing new insights into the pathogenesis of gout.The translation of genetic signals into mechanistic knowledge requires experimental studies, which are gradually being conducted in loci such as and