ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Abstract

As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.

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

“…Thus it could be predicted that changes in CHAC2 expression would disrupt glutathione homeostasis altering urate secretion/reabsorption in the kidney. Finally, we note that there was no evidence for a regulatory effect at ABCG2 which is consistent with the strong evidence supporting p.Gln141Lys ( rs2231142 ) as the dominant causal variant at that locus [13]. A similar scenario exists at GCKR where p.Leu446Pro ( rs1260326 ) is the maximally-associated variant (Figure S5).…”

“…There has, however, been little progress on understanding the molecular basis of the association for the various loci. Probable causal genes have been identified at only about one fifth of the 36 loci [10–12], with strong evidence for causality for variants identified at ABCG2 ( rs2231142 ; Q141K) and PDZK1 ( rs1967017 ) [11, 13–17].…”

The systems biology of uric acid transporters

“…Although many of these uric acid transporters are most highly expressed in the kidney, where they function in urate handling by the proximal tubule resulting in net renal excretion (Fig. 1), they are also expressed in extrarenal tissues, such as the intestine [22–24]. In the setting of renal disease, intestinal excretion of urate appears to become important for maintaining uric acid levels, suggesting some sort of mechanism for remote communication between the failing kidney and intestine with respect to uric acid homeostasis (Fig.…”

“…Unlike most of the transporters discussed here, which largely mediate renal tubular influx and efflux of uric acid, ABCG2 is highly expressed in intestinal tissue [22] where it excretes up to one third of all uric acid and is thus thought to be the main extrarenal site of uric acid elimination [24,33]. In addition, ABCG2 knockout mice have lower intestinal excretion and higher levels of serum uric acid [34], whereas a common ABCG2 variant, Q141K (rs2231142), is associated with an increase of uric acid levels among European and East Asian populations [23,35,36].…”

A non-coding genetic variant maximally associated with serum urate levels is functionally linked to HNF4A-dependent PDZK1 expression

“…PDZK1). The well-characterized ABCG2 p.Gln141Lys protein variant is highly likely to be causal (10). However, the causal genes and genetic variants at the considerable majority of the serum urate loci remain unconfirmed (11).…”