Skip to navigation Skip to main content Skip to footer

Approved Research

Estimating the genetic overlap between gout, serum urate and comorbidities.

Principal Investigator: Dr Richard Reynolds
Approved Research ID: 59690
Approval date: September 2nd 2020

Lay summary

Hyperuricemia (serum urate (SU) > 6.8 mg/dL) is necessary but not sufficient to cause gout, as studies show for every person with gout, there are five to ten times as many with asymptomatic hyperuricemia. Monosodium urate crystals (MSU) activate inflammatory immune cells (e.g. monocytes/macrophages), which potentiate acute gout attacks. MSU deposits have been found in joints of people with asymptomatic hyperuricemia and in asymptomatic gout patients. These observations suggest a genetic etiology for gout with two primary sources. The first is a genetic predisposition that leads to high serum urate, which then causes gout. The second is a genetic predisposition that is either conducive to or resistant to acute inflammation that may or may not relate to serum urate levels. Almost all large effect genes associated with gout risk also contain variants associated with serum urate. These genes encode proteins in the kidney and gut which transport serum urate. This observation suggests that the genetics of gout is mediated by the direct effect of these variants on serum urate levels. In this project we propose to test the hypothesis that the genetics of gout is described completely by serum urate.

We will use two main analytical approaches to test our hypothesis. If the genetics of gout is solely due to serum urate we can make two predictions. The first prediction is that in a two variable model of gout risk, serum urate will explain all gout risk and the genetic marker will explain none. We can reject the hypothesis that gout genetic risk is explained solely by serum urate if the genetic marker is significantly associated with gout beyond the effect explained by serum urate. The second prediction is that if all genetic risk loci for serum urate and gout are identical and shared then the genetic correlation, estimated using quantitative genetic methods, should not be significantly different than one. Otherwise, we can reject the hypothesis that gout risk is explained solely by serum urate. Therefore, if our study predictions under our working hypothesis are rejected, an alternative genetic model of gout risk is warranted. Our study will allow us to discover novel loci harboring variants associated with gout that implicate other pathways in addition to serum urate absorption and excretion, that could be cardio-metabolic or inflammatory. This outcome would be consistent with gout candidate gene studies that have identified risk loci with inflammatory functions.