FRI0231 Study of urate transporters in primary hyperuricemia and gout
Authors: B. Stiburkova, K. Pavelcova, J. Bohata, K. Kozakova, L. Petru, J. Zavada, K. Pavelka
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The urate transporters are one of the main genetic determinants of serum uric acid concentrations. <h3>Objectives</h3> In this study we investigated the effects of non-synonymous allelic variants of urate transporters in a cohort of patients with primary gout and/or asymptomatic hyperuricemia. <h3>Methods</h3> The cohort consisted of 165 gout patients (151 men, 14 women); 58 hyperuricemic individuals (39 men/19 women); 115 normouricemic controls were used for comparison. Gouty arthritis was diagnosed according to the 1977 preliminary criteria of the American College of Rheumatology. Coding regions of <i>ABCG2</i>, <i>SLC2A9</i>, <i>SLC22A11</i>, <i>SLC22A8</i>, <i>SLC17A3</i>, and <i>SLC17A1</i> genes were amplified and sequenced directly. To estimate the functions of the identified non-synonymous allelic variants, we used the protein prediction algorithms. <h3>Results</h3> In <i>ABCG2</i> gene, we detected nine non-synonymous variants (two common, seven rare including one novel): p.V12M, p.Q141K, p.R147W, p.T153M, p.K360del, p.F373C, p.T434M, p.S476P and p.D620N. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared to the European-origin population (0.09) and was significantly more common among gout patients than among normouricemic controls (OR=3.15, p&lt;0.0001). In addition, patients with non-synonymous <i>ABCG2</i> allelic variants had an earlier onset of gout (41.5 vs. 48 years, p=0.0478) and a greater likelihood of a familial history of gout (42% vs. 26%, OR=2.02, p=0.043)<sup>1</sup>. We identified novel intron variant c.689+1G&gt;A which is associated with two abnormal splicing variants, leading to premature introduction of the stop codon, mislocalized ABCG2 signal on plasma membrane and no urate uptake activity<sup>2</sup>. In <i>SLC2A9</i> gene, seven missense variants were identified (six common, one rare): p.A17T, p.G25R, p.T275M, p.D281H, p.V282I, p.R294H, and p.P350L. In <i>SLC17A3</i>, the analysis revealed common allelic variants p.A100T and p.G279R. Rare non-synonymous variants p.V202M and p.R343L were found in <i>SLC22A11</i>. Only one common missense variant p.T269I was identified in <i>SLC17A1</i>. In <i>SLC22A8</i> sequencing revealed three rare variants: p.R149C, p.V448I and p.R513G. The precise impact of <i>SLC22A11</i>, <i>SLC22A8</i>, <i>SLC17A3</i>, and <i>SLC17A1</i> in the context of hyperuricemia and gout in our cohort is unclear and will be further studied include functional characterisation of selected dysfunctional variants. <h3>Conclusions</h3> Genetic variants of <i>ABCG2</i>, common and rare, increased the risk of gout and had a significant effect on earlier onset of gout and the presence of a familial gout history. Genotyping the rare variants of <i>ABCG2</i> along with its common variants is essential for evaluating the individual risk for gout. <h3>References</h3> [1] Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford)2017Nov 1;56(11):1982–1992. [2] Stiburkova B, et al. Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: biochemical, molecular genetics and functional analysis. Rheumatology (Oxford)2016Jan;55(1):191–4. <h3>Acknowledgements</h3> This study was supported by the grant from the Czech Republic Ministry of Health AZV 15–26693A. <h3>Disclosure of Interest</h3> None declared