The Global Urate Genetics Consortium (GUGC) has identified 28 genome-wide significant urate concentration–associated loci. The latest genome analysis underscores the importance of metabolic control in urate production.
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The GUGC study included more than 110,000 individuals and related the identified loci to prevalent and ACR criteria–confirmed incident gout. The authors acknowledged that the definition of gout varied across several cohorts, but explained that potential misclassifications were unlikely to lead to false-positive results. As expected, alleles associated with increased serum urate concentration were also associated with increased risk of gout. The study confirmed the presence of urate concentration–associated single-nucleotide polymorphisms (SNPs) that have been described in previous genome-wide association studies (GWAS).
The current study, published in Nature Genetics, describes the functional and biochemical implications of the new loci.1 The authors identified loci linked to known urate transporters expressed in the renal proximal tubules, as well as loci linked to glucose metabolism and/or insulin response. The study was unable to identify a significant aggregate effect of urate concentration–associated loci on measures of insulin resistance or glycemic traits.
In the discussion, the authors write: “Our finding that gene loci implicated in glucose homeostasis influence serum urate concentrations fits with the observation that drugs that decrease insulin resistance, such as thiazolidinediones and metformin, tend to decrease serum urate levels. Thus, the identification of new gene loci in the present study may open new avenues for research to improve the treatment and prevention of gout.”
As an example of potential new drug targets, the large genome analysis identified loci associated with the inhibins/activins growth factor system.
Veronique Vitart, PhD, of the University of Edinburgh in the United Kingdom and Murielle Bochud, MD, PhD, of the University Institute of Social and Preventive Medicine in Lausanne, Switzerland, are members of the GUGC. They discussed the study and its implications with The Rheumatologist via email. They wrote: “Unlike the majority of the loci identified in the first, smaller scale, genome-wide association studies for serum urate level, none of the newly identified loci is a solute transporter. These additional loci are, in majority, transcription, signaling, or growth factors with a broad spectrum of actions, each having a small effect in modulating urate level (<0.5% sex- and age-adjusted urate variance). The clinical utility of the genetic risk score that can be derived from the total of the urate variants is still limited.”
Dr. Pullen is a medical writer based in the Chicago area.