AB1358 THE EFFECT OF VARIANTS IN THE ABCG2 GENE IN PATIENTS WITH GOUT AND CHRONIC KIDNEY DISEASE
Authors: K. Pavelcova, J. Masinova, J. Vachek, H. Ciferská, B. Stiburkova
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The ABCG2 protein (encoded by the <i>ABCG2</i> gene) is an important transporter of uric acid in the kidneys and, to a lesser extent, in the intestine. Genetic variants in <i>ABCG2</i> are known to be associated with the pathogenesis of gout and a more severe course of chronic kidney disease (CKD). <h3>Objectives:</h3> The aim of our study was to map the occurrence and evaluate the effect of variants in <i>ABCG2</i> in patients with primary hyperuricemia, gout and chronic kidney disease. <h3>Methods:</h3> We assembled two cohorts. The first included patients with primary hyperuricemia (178 individuals) and primary gout (300 individuals). The second cohort included 160 patients with CKD in stage 4 to 5 (requirement of renal replacement therapy), of which 32 individuals had gout as a comorbidity. Using PCR amplification and Sanger sequencing, we analyzed all exons and exon-intron boundaries of the ABCG2 gene (transcript ENST00000650821). We monitored the clinical manifestation and mortality of patients from the CKD cohort for a period of 16 months. <h3>Results:</h3> In both cohorts, the common variant p.Q141K, which according to many previous studies leads to a reduced transport capacity of ABCG2 and to hyperuricemia, occurred. The minor allelic frequency (MAF) of this variant is 0.094 in the European population (Ensembl database). We found a MAF of 0.22 in the gout cohort and 0.114 in the CKD cohort. In the gout cohort, we also found 16 rare nonsynonymous variants: p.M71V, p.G74D, p.M131I, p.R147W, p.T153M, p.I242T, p.R236X, p.K360del, p.F373C, p.F373del, p.T421A, p.T434M, p.S476P, p.A528T, p.S572R, and p.D620N [1]. According to a functional study, the following variants have a pathogenic impact on the function of the urate transporter: p.M131I, p.R147W, p.T153M, p.R236X, p.F373C, p.T434M, p.S476P, and p.S572R [2,3]. Regarding the CKD cohort, we detected the following pathogenic variants: p.R45Q, p.M131I, p.R236X, and p.E344D. In contrast to previous studies, in our CKD cohort, variants were not associated with increased mortality or more severe clinical manifestations during the 16-month follow-up period [4]. <h3>Conclusion:</h3> Our data showed that the common variant p.Q141K and other rare variants in the <i>ABCG2</i> gene are a significant risk factor for the development of hyperuricemia and gout. In the CKD cohort, we did not detect a pathogenic impact of variants in <i>ABCG2</i>, contrary to our hypothesis, which can be explained by the fact that the cohort was too small and that the data may have been biased by the ongoing COVID-19 pandemic. <h3>REFERENCES:</h3> [1] Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford). 2017 Nov 1; 56(11):1982-1992. [2] Toyoda Y, et al. Functional characterization of clinically-relevant rare variants in ABCG2 identified in a gout and hyperuricemia cohort. Cells. 2019 Apr 18;8(4). [3] Toyoda Y, et al. Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout. Int J Mol Sci. 2021 Feb 16;22(4):1935. [4] Nakashima A, et al. Dysfunctional ABCG2 gene polymorphisms are associated with serum uric acid levels and all cause mortality in hemodialysis patients. Hum Cell. 2020 Jul;33(3):559-568. <h3>Acknowledgements:</h3> This study was supported by the project for conceptual development of research organization (Institute of Rheumatology, 00023728) and by the grant from the Czech Republic Ministry of Health (NU22-01-00465). <h3>Disclosure of Interests:</h3> <b>None declared.</b>