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

Abstract

IntroductionThere 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.MethodsA 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.ResultsA 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).ConclusionsOur 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.

Twenty-eight loci that influence serum urate levels: analysis of association with gout

“…Evidence for association with gout at SLC22A12 strengthened our previous observation. However, the additional samples genotyped here weakened evidence for association of SLC22A11 with gout in Polynesian3 and, consistent with our previous report,3 provided no evidence for association in NZ European (OR=1.04, p=0.59).…”

“…INHBC is also consistently associated in European and Polynesian with OR=∼1.15, although with a lower effect size than GCKR (table 1). 6 By contrast, SLC22A11 is not consistently associated with gout, with the statistically strong evidence for association reported in Köttgen et al 6 in European (OR=1.14, p=2.3×10 −5 ) not replicated by us (table 1; OR=1.04, p=0.59) 3. The still weaker evidence for association of SLC16A9 with gout in Köttgen et al 6 (OR=1.10, p=0.017) was also not replicated by us (table 1; OR=1.01, p=0.89).…”

“…The lack of association could indicate pleiotropic effects (eg, at PDKZ1 ), and understanding these effects should yield insights into the aetiology of gout. The population-specific effects at ABCG2 , SLC22A11 , SLC22A12 and LRP2 in gout3 7 9 10 also highlight the necessity for transancestral studies, especially in populations with earlier onset and more severe gout, and a higher prevalence of comorbidities, such as those of Filipino and New Zealand (NZ) Ma¯ori and Pacific ancestry who have a prevalence of gout double that of European Caucasian 11–13…”

Predicting allopurinol response in patients with gout

“…DNA extraction and genotyping by TaqMan ® assays ( Applied Biosystems , Foster City) of SNPs rs11942223 (SLC2A9), rs2231142 (ABCG2), rs1183201 (NPT1/SLC17A1) and rs3825018 (URAT1) has been described elsewhere . Details of the genotypic data available for analysis are presented in Supplementary Table S2.…”

The Molecular Physiology of Uric Acid Homeostasis

“…The SLC22A11/SLC22A12 locus has been implicated in GWAS in determining SUA in a number of different populations (16,67,68). At the functional level, urate transport experiments show that one coding polymorphism, G65W, is a partial loss-of-function allele; each copy of this allele is associated with an ∼1.0 mg/dL drop in SUA (67).…”