Population‐Specific Resequencing Associates the ATP‐Binding Cassette Subfamily C Member 4 Gene With Gout in New Zealand Māori and Pacific Men

Objective There is no evidence for genetic association of the organic anion transporters (OAT) 1-3 (SLC22A6, SLC22A7, SLC22A8) and multi-drug resistance protein 4 (MRP4; ABCC4) with serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand (NZ) has the highest prevalence of gout worldwide. Our aim was to determine if there were any Polynesian population-specific genetic variants in the SLC22A6-8 and ABCC4 genes associated with gout. Participants and Methods All participants had ≥3 self-reported Māori and/or Pacific grandparents. From the total sample set of 1808 participants, 191 hyperuricaemic and 202 normouricaemic individuals were resequenced over the four genes with the remaining 1415 individuals used for replication. Regression analyses were performed adjusting by age, sex and Polynesian ancestry. To study the functional effect of non-synonymous variants ABCC4 transport assays were done in Xenopus laevis ooctyes. Results A total of 39 common variants were detected, with an ABCC4 variant (rs4148500) significantly associated with hyperuricemia and gout. Rs4148500 was monomorphic (for the protective major allele) in Europeans. There was evidence for association for rs4148500 with gout in the resequenced samples (OR=1.62, P=0.012) that was replicated (OR=1.25, P=0.033) and restricted to males (ORMales=1.43, P=0.001; ORFemales=0.98, P=0.89). The gout risk allele was associated with FEUA in males (β=-0.570, P=0.01). A rare population-specific variant (P1036L) with strong functional consequence reduced the uric acid transport activity of ABCC4 by 30%. Conclusion Association of ABCC4 with gout and FEUA is consistent with the established role of MRP4 as a unidirectional renal uric acid efflux pump. This article is protected by copyright. All rights reserved.