THU0539 Population-Specific Resequencing Reveals Association of The ABCC4/MRP4 Gene with Gout in New Zealand Māori and Pacific Men
Authors: T. Merriman, J. Boocock, E. Stahl, M. Cadzow, A. Phipps-Green, R. Topless, J. Harre Hindmarsh, D. Mount, L. Stamp, N. Dalbeth, H. Choi, C. Tanner
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> Genetic variants in uric acid transporters that control serum urate levels have been identified in Europeans by genome-wide association studies [1]. However there is no evidence for association with serum urate (or gout) with the organic anion transporters (OAT) 1–3 (<i>SLC22A6, SLC22A7</i> and <i>SLC22A8</i>) and multi-drug resistance protein 4 (MRP4) encoded by <i>ABCC4</i>; all four transporters have been implicated in uric acid secretion [2]. The Māori and Pacific (Polynesian) population of New Zealand (NZ) has the highest prevalence of gout worldwide and exhibits lower fractional excretion of uric acid (FEUA) than Europeans. <h3>Objectives</h3> To identify any Polynesian population-specific genetic variants in the <i>SLC22A6–8</i> and <i>ABCC4</i> genes associated with gout. <h3>Methods</h3> All participants had ≥3 self-reported Māori and/or Pacific grandparents. From the total sample set of 1808 individuals, 191 hyperuricaemic (highest urate levels) and 202 normouricaemic (lowest urate levels) individuals were selected and resequenced over a total of 24.3 kb of promoter, exon and 39 and 59 untranslated region DNA within the four genes. Replication genotyping for <i>rs4148500</i> was done using Taqman over the remaining 1415 individuals. Logistic regression association analysis with gout or hyperuricaemia (≥0.36 mmol/L in women, ≥0.42 mmol/L in men) as outcome, or linear regression with FEUA or serum urate as outcome, was performed adjusting by age, sex and Polynesian ancestry. <h3>Results</h3> A total of 39 common variants were detected with one in <i>ABCC4</i> (<i>rs4148500</i>) significantly associated with hyperuricaemia and gout. There were substantial differences in allele frequency between Western (Samoan, Tongan, Niuean, Tokelaun) and Eastern (NZ and Cook Island Māori) Polynesian samples – adjusting for ancestry revealed evidence for association with gout in the resequenced samples (OR=1.62, <i>P</i>=0.012 for <i>rs4148500</i>). The association of <i>rs4148500</i> with gout was replicated (OR=1.25, <i>P</i>=0.033) and was restricted to males (OR<sub>Males</sub>=1.43, <i>P</i>=0.001; OR<sub>Females</sub>=0.98, <i>P</i>=0.89). The gout risk allele was associated with FEUA in males (b=-0.570, <i>P</i>=0.01) and there was a trend towards association with serum urate in the male controls (b=0.013, <i>P</i>=0.07). The Ensembl database revealed that the variant was monomorphic (for the protective major allele) in Europeans. <h3>Conclusions</h3> This is the first report of a genetic factor specifically contributing to the increased risk of gout in men of Māori and Pacific ancestry in NZ. Association of <i>ABCC4</i> with gout and FEUA is consistent with the established role of MRP4 as a unidirectional urinary uric acid efflux pump of uric acid [3]. <h3>References</h3> Kottgen et al. Nat Genet 2013;45:145 Mandal and Mount. Ann Rev Physiol 2015;77:323 Van Aubel et al. Am J Physiol 2005;288:F327 <h3>Acknowledgement</h3> The New Zealand Health Research Council, Lottery Health New Zealand, Arthritis New Zealand and the National Institute of Health (United States) are thanked for funding this study. <h3>Disclosure of Interest</h3> T. Merriman Grant/research support from: ArdeaBio, J. Boocock: None declared, E. Stahl: None declared, M. Cadzow: None declared, A. Phipps-Green: None declared, R. Topless: None declared, J. Harre Hindmarsh: None declared, D. Mount: None declared, L. Stamp: None declared, N. Dalbeth Grant/research support from: Fonterra, ArdeaBio, AstraZeneca, Consultant for: Takeda, Menarini, Teijin, Pfizer, Crealta, Cymabay, H. Choi: None declared, C. Tanner: None declared