Background: Recently, SLC22A12 has been identified as a urate-anion exchanger in the human kidney.
Methods: We screened for polymorphisms of SLC22A12 and conducted an association study between genetic polymorphisms and urate levels in an epidemiologic cohort representing the general population in Japan. Functional significance of mutations was assessed by oocyte expression analysis.
Results: We found five missense, one nonsense, and one deletion mutations [R90H, A226V, R228E, W258Stop, Q312L, D313A (deletion of 313D-333P), and R477H] in 24 subjects with hypouricemia recruited from an epidemiologic cohort (Suita Study) representing the general population in Japan (N= 1875). A statistical analysis indicated that the 90H (N= 14), 477H (N= 5), and 258Stop (hetero + homo N= 82 + 3) alleles were associated with hypouricemia. The alleles 228E and 313A (deletion of 313D-333P) were found just once in the total population. In vitro oocyte expression analysis indicated that 313A (deletion of 313D-333P) had no urate transport activity, indicating that this is a newly identified mutation for idiopathic renal hypouricemia. Intriguingly, the allele frequency of 258Stop was unexpectedly high (2.37%). However, this inactivating mutation does not seem to be harmful in the general population. The effects of common polymorphisms of SLC22A12 were also investigated. Based on linkage disequilibrium, 16 common polymorphisms were categorized into six distinct groups, and six representative genotypes were determined. None of these six common polymorphisms affected the serum uric acid level. A haplotype analysis also suggested that these common genotypes/haplotypes were not important in determining the serum uric acid levels in the general population.
Conclusion: SLC22A12 is a major gene for hypouricemia but not hyperuricemia in Japanese.