FRI0231 Study of urate transporters in primary hyperuricemia and gout. (12th June 2018)

• Record Type: Journal Article
• Authors: Stiburkova, B.; Pavelcova, K.; Bohata, J.; Kozakova, K.; Petru, L.; Zavada, J.; Pavelka, K.
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 2
• Page Start: 657
• Page End: 657
• Publication Date: 2018-06-12
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-eular.5311
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: The urate transporters are one of the main genetic determinants of serum uric acid concentrations. Objectives: 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. Methods: 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 ABCG2, SLC2A9, SLC22A11, SLC22A8, SLC17A3, and SLC17A1 genes were amplified and sequenced directly. To estimate the functions of the identified non-synonymous allelic variants, we used the protein prediction algorithms. Results: In ABCG2 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<0.0001). In addition, patients with non-synonymous ABCG2 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) 1 . We identified novel intron variant c.689+1G>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 2 . In SLC2A9 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 SLC17A3, the analysis revealed common allelic variants p.A100T and p.G279R. Rare non-synonymous variants p.V202M and p.R343L were found in SLC22A11 . Only one common missense variant p.T269I was identified in SLC17A1 . In SLC22A8 sequencing revealed three rare variants: p.R149C, p.V448I and p.R513G. The precise impact of SLC22A11, SLC22A8, SLC17A3, and SLC17A1 in the context of hyperuricemia and gout in our cohort is unclear and will be further studied include functional characterisation of selected dysfunctional variants. Conclusions: Genetic variants of ABCG2, 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 ABCG2 along with its common variants is essential for evaluating the individual risk for gout. References: [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. Acknowledgements: This study was supported by the grant from the Czech Republic Ministry of Health AZV 15–26693A. Disclosure of Interest: None declared