A genome-wide search for genes affecting serum uric acid levels had demonstrated that the heritability of serum urate levels is about 63% [7
]. Until recently, our knowledge of the genetics of gout was limited to the rare genetic mutations discussed above. In the last few years, development of new tools to investigate the human genome has permitted important advances in our understanding of disease. Among them, genome-wide association studies (GWAS) are a recently developed research technique to identify DNA polymorphisms distributed across different large populations, and they permit the determination of common genetic factors that influence health and disease. Since 2008, different GWAS identified nine DNA loci associated with serum urate concentration, with four linked to gout in several populations [8
]. These new data led researchers to determine the function of genes associated with the loci and their relationship with urate levels and gout, along with the relevant single nucleotide polymorphisms (SNPs) for each involved gene. The four loci associated with gout all correspond to urate transporters located in the epithelial cells of renal proximal tubules ().
Urate transporters in proximal tubule epithelial cells
The locus most strongly linked to gout corresponds to the glucose transporter 9 (GLUT9), also known as the solute carrier 2A9 (SLC2A9). In contrast to the three other loci that are linked to an increased risk of gout, several variants of GLUT9 are linked to a reduced risk. The transporter is predominantly expressed in liver and kidney but is also found in chondrocytes from human cartilage, where, in gout, urate is deposited. It was initially identified as a glucose/fructose transporter [12
], then functional studies demonstrated that SLC2A9 was also able to transport urate in renal reabsorption [13
]. SLC2A9 exists as two isoforms that differ by the length of their cytoplasmic domain and by their apical or basolateral localization in renal epithelial cells [14
]. Several variants of SLC2A9 are associated with hypouricemia and a lower risk of gout [13
]. It seems that instead of impairing the protein function, the variants might influence the relative expression level of the two isoforms, leading to reduced reabsorption and increased excretion of uric acid [13
The second locus linked to gout corresponds to the gene encoding the urate transporter 1, URAT1 (also named solute carrier 22A12). The gene was cloned in 2002 and immediately identified as a urate-organic anion exchanger, re-absorption being triggered by high intracellular loads of lactate and several other organic anions [16
]. Localized in the apical membrane of kidney cells, URAT1 is one of the essential transporters involved in urate reabsorption. URAT1 SNPs were first linked to hypouricemia [16
]. Since then, several mutations in the URAT1 gene have been linked to hyperuricemia and gout in different populations [18
], and a GWAS performed in 2009 linked the locus to an increased risk of gout [9
]. The molecular mechanism causing this urate level increase has still not been elucidated.
The third locus linked to gout encodes the renal sodium phosphate transport protein 1 (NPT1, or solute carrier 17A1), which is localized at the apical membrane of renal proximal tubules. It was initially identified in 1993 as a sodium-phosphate cotransporter [21
]. Following its linkage to gout by GWAS [9
], it was shown to also be a voltage-driven urate transporter involved in urate secretion [22
]. The studied protein variant exhibited lower urate transport activity compared with the wild-type protein [22
]. Then, several other SNPs in the NPT1 gene were associated with increased risk of gout in humans [23
The last locus linked to gout corresponds to the ABCG2 gene, a transporter initially known for its involvement in resistance to chemotherapy. We discuss below the unexpected association between ABCG2 SNPs and gout. As a transporter previously associated with multidrug resistance, the identification of a physiological role for ABCG2 has opened up new avenues in which this protein could become an important target for clinical therapy.