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There is inconsistent association between urate transporters  SLC22A11  (organic anion transporter 4 (OAT4)) and  SLC22A12  (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) Māori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the  SLC22A11/SLC22A12  locus for association with risk of gout in NZ sample sets.    Methods  A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata.    Results  A haplotype block 1 SNP ( rs17299124 ) (upstream of  SLC22A11 ) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR = 3.38,  P  = 6.1 × 10 -4 ; OR = 0.91,  P  = 0.40, respectively) sample sets. A protective block 1 haplotype caused the  rs17299124  association (OR = 0.28,  P  = 6.0 × 10 -4 ). Within haplotype block 2 ( SLC22A11 ) we could not replicate previous reports of association of  rs2078267  with gout in European Caucasian (OR = 0.98,  P  = 0.82) sample sets, however this SNP was associated with gout in Polynesian (OR = 1.51,  P  = 0.022) sample sets. Within haplotype block 3 (including  SLC22A12 ) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR = 0.80,  P  = 0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR = 0.63,  P  = 0.028) but risk in European Caucasian samples (OR = 1.33,  P  = 0.039).    Conclusions  Our analysis provides evidence for multiple ancestral-specific effects across the  SLC22A11/SLC22A12  locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.

arthritis research and therapy

Association analysis of the SLC22A11 (organic anion transporter 4) and SLC22A12 (urate transporter 1) urate transporter locus with gout in New Zealand case-control sample sets reveals multiple ancestral-specific effects