Blanka Stiburkova1,3, Katerina Pavelcova1,2, Lenka Petru1,2, Jakub Zavada1 and Karel Pavelka1
1 Institute of Rheumatology, Prague, Czech Republic, 2 Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 3 Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Objective: The urate transporters are one of the main genetic determinants of serum uric acid concentrations. Primarily nonsynonymous polymorphisms in ABCG2 and SLC2A9 are clinically important for the development of primary gout and hyperuricemia. In this study we investigated the effects of allelic variants of urate transporters in a cohort with primary gout and/or hyperuricemia.
Methods: The cohort was recruited in the Institute of Rheumatology, gout was diagnosed in 165 subjects (151 men / 14 women) and hyperuricemia in 58 subjects (39 men / 19 women). Coding regions of ABCG2, SLC2A9, SLC22A11, SLC22A8, SLC17A3, and SLC17A1 genes were amplified and sequenced directly.
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 gene, 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 gene, sequencing revealed three rare non-synonymous variants: p.R149C, p.V448I and p.R513G.
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. 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 characterization of selected dysfunctional variants. Although knowledge of renal urate handling has been increased, current evidence is insufficient to fully understand the precise mechanism governing the bi-directional transport of urate.
References: 1. Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford). 2017 Nov 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). 2016 Jan;55(1):191-4.
Acknowledgements: This study was supported by the grant from the Czech Republic Ministry of Health AZV 15-26693A.