Background/Purpose: The urate transporters are one of the genetic determinants of serum uric acid concentrations. In the present study, we describe the analysis of sequencing variants in the ABCG2, SLC17A3, SLC22A11 and SLC17A1 genes, physiologically important urate transporters whose dysfunction can play a role in pathogenesis of hyperuricemia, in a cohort with primary hyperuricemia and gout.

Methods: The cohort consisted of 150 individuals: 32/118 primary hyperuricemics/gout. The definition of hyperuricemia was as follows: >420/360 µmol/l at two repeated measurements at intervals of at least 4 weeks in men/women. Gouty arthritis was diagnosed according to the 1977 preliminary criteria of the American College of Rheumatology for acute arthritis of gout. Patients suffering from secondary gout were excluded. In total, 7050 PCR amplicons were sequenced directly: 10 for SLC17A3, 10 for SLC17A1, 10 for SLC22A11, 17 for ABCG2.

Results: In the SLC17A3 gene were found 7 intronic/3 exon variants (2 non-synonymous rs1165165, rs56027330), in SLC17A1 7 intronic/1 non-synonymous exon variant (rs1165196) and in SLC22A11 3 intronic/4 exon variants (2 non-synonymous rs201209258, rs75933978). Allele frequencies for all exon and intron variants found in SLC17A1, SLC17A3 and SLC22A11 genes were not statistically significant compare to general Caucasian population. In the ABCG2 gene, 16 intronic variants were detected. In the case of c.689+1G>A, related to an individual with severe gouty phenotype, two abnormal splicing variants were identified: a) r.[532_689del]; b) r.[532_689del], r.[944_949del]. Identified deletions lead to frameshift and premature stop codon introduction¹. From the 9 exon variants detected, there were 7 non-synonymous: p.V12M (rs2231137), p.Q141K (rs2231142), p.R147W (rs372192400), p.T153M (rs753759474), p.F373C (rs752626614), p.T434M (rs769734146) and p.D620N (rs34783571). Heterozygous p.V12M variant was detected in 7 individuals. Heterozygous variant p.R147W, p.T153M, p.F373C, p.T434M and p.D620N was detected once, variant p.D620N was detected twice also in heterozygous state. All these five allelic variants were in silico predicted using Polyphen, Sift and Provean program as a probably damaging and were not detected in control cohort of 150 normouricemia subjects. The p.Q141K, previously functionally characterized variant with a strong effect on uric acid secretion impairment, was in cohort of hyperuricemic/gout patients presented with significantly higher minor allele frequency (MAF)=0.19 (42 heterozygotes/5 homozygotes), than in population of European origin (MAF=0.09) and world-wide population (MAF=0.12).

Conclusion: Our results show that genetic factor ABCG2 should be considered as one of the common risks for hyperuricemia/gout. In clinical practice, ABCG2 dysfunction can be estimated easily by genotyping and these findings will help to recognize a trait of hyperuricemia at a very early stage. References: 1. 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: Czech Republic Ministry of Health AZV 15-26693A.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-analysis-of-urate-transporters-abcg2-slc17a3-slc22a11-and-slc17a1-in-primary-hyperuricemia-and-gout/