*6.1. The Role of ABCG2 Variants in Hyperuricemia and Gout*

One of the important roles of ABCG2 is the clearance of uric acid, the end-product of purine metabolism. Interestingly, uric acid was not identified as a physiologically relevant endogenous substrate of ABCG2 until genome-wide association (GWA) studies revealed the association between the Q141K polymorphism in the *ABCG2* gene and gout [151], a disease characterized by inflammatory arthritis of the joints caused by urate deposition and crystal formation in the synovial fluid. This condition can develop as a result of either

hepatic overproduction or diminished excretion of uric acid. The Q141K polymorphism has been established as one of the strongest genetic determinants for high serum urate levels (hyperuricemia) and gout development [37,56,103,105,106,119,152]. Surprisingly, Q141K polymorphism (and its murine ortholog Q140K) diversely affected ABCG2 function in intestine and kidney, i.e., while ABCG2-mediated intestinal urate clearance was substantially reduced (or abolished), the function of ABCG2 was preserved in the kidney, suggesting a tissue-specific regulation/trafficking and differential pathology of this ABCG2 variant [58]. Ironically, another GWA study demonstrated an association between the Q141K polymorphism and a worse response to allopurinol [153], which is the first-line treatment for chronic gout. Allopurinol and its active metabolite, oxypurinol, are intended to lower uric acid levels by inhibiting xanthine oxidase, the major enzyme for the production of uric acid. Allopurinol and oxypurinol have been reported to be transported substrates of ABCG2; thus, they are retained in cells expressing the Q141K ABCG2 as compared to wt-expressing cells. A subsequent study demonstrated that ABCG2 transports oxypurinol, but not allopurinol itself [154]. Further pharmacogenomic analyses established the link between presence of the Q141K allele and increased risk of poor response to allopurinol [155–157], but the underlying mechanism, how Q141K influences allopurinol disposition and the clinical response, is yet to be clarified.

Several other ABCG2 mutations/polymorphisms have been identified as genetically associated risk factors for gout incidence (see Table 1). These include Q126X, R147W, T153M, and D620N [56,103,105–107]. No association between V12M and increased risk of gout have been established [56,103]; indeed, one study reported a protective effect of this SNP on gout susceptibility [105]. Recently, using blood samples from patients with hyperuricemia or gout, in addition to Q141K, we found three other mutations (M71V, R236X, and R383C) associated with reduced protein levels in the RBC membrane [112]. It is worth mentioning that most of these ABCG2 SNPs connected with hyperuricemia or gout belong to Class 1 or Class 2.
