POS0354 DETECTION OF ABCG2 VARIANTS IN ENCODING OF URATE TRANSPORTERS ASSOCIATED WITH THE HYPERURICEMIA IN HAEMODIALYSIS PATIENTS
Authors: H. Ciferska, K. Pavelcova, J. Vachek, B. Stiburkova
Journal: Annals of the Rheumatic Diseases (2021)

Background: Hyperuricemia is associated with gout, hypertension, cardiovascular diseases and renal disease. The presence of chronic kidney disease (CKD) is associated with low excretion of the uric acid as the homeostasis in maintaining of serum levels of uric acid is impaired. Progression of CKD is connected to hyperuricemia and lowering levels of the uric acid is one of the most important goals in clinical treatment. Dysfunctional variants of ATP-binding cassette transporter subfamily G member 2 (ABCG2), a major urate transporter in the kidney and intestine, are the major causes of hyperuricemia and gout. A recent studies found that ABCG2 is also a major transporter of uremic toxins and ABCG2 dysfunctional variants are risk genetics factors for mortality in hemodialysis patients. Objectives: The aim of the present study was to investigate the frequencies of ABCG2 variants in cohort of hemodialysis patients. Methods: In this retrospective one centre study 167 patients (age=79,8±11,03;female=74) with end-stage CKD (pre-dialysis n=86; dialysis n=79) were collected. Peak urate levels were 456,3±113,6 μmol/l in pre-dialysis and 572,93±114,56 μmol/l in dialysis. ABCG2 coding regions were analyzed from genomic DNA, as we described previously (1). The reference sequence was defined as version ENST00000237612.7, the reference protein sequence was defined as Q9UNQ0. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions. Results: In the CKD cohort, 15 intronic and seven non-synonymous allelic exonic variants were detected: two common (rs2231137/p.V12M; rs2231142/p.Q141K), five ultra rare and/or rare (rs142634180/p.R45Q, rs759726272/p.M131I, rs140207606/p.R236X, rs138606116/p.G354R, rs138892154/p.A607V), and one novel (p.E344D). Common variant p.V12M, previously reported as protective allele, was detected in 12 heterozygous patients with. The p.Q141K variant, detected in the homozygous stage in three patients and in 31 patients as heterozygous variant. Heterozygous rare variants p.R45Q, p. G354R, p.A607V, and novel variant p.E344D were detected in one heterozygous patient each; heterozygous p.M131I and p.R236X in two patients. Conclusion: In this study, significantly higher frequency of dysfunctional ABCG2 variants, common and rare, in comparison with common European population, were identified. On the other hand, the frequency of probably protective allele variant p.V12M was significantly lower in CKD cohort (MAF in our cohort = 0,036/MAF in the European population = 0,061). Further analysis of ABCG2 association with CKD events via ABCG2 inflammation role is necessary. In conclusions, our finding of one novel, five rare and two common non-synonymous ABCG2 allelic variants in a sample of 167 CKD patients suggests that the ABCG2 variants should be considered a risk factor for CKD. References: [1]Toyoda Y, et al. Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort. Cells . 2019;18;8(4). Acknowledgements: This study was supported by the grant from the Czech Republic Ministry of Health RVO 00023728. Disclosure of Interests: None declared