Background/Purpose: Gout, a condition arising from hyperuricemia, is considered as both a metabolic disorder and an autoinflammatory disease. Genetic factors are estimated to contribute approximately 40% to serum uric acid levels. Among urate transporters, ABCG2 (ATP-binding cassette sub-family G member 2) plays a crucial role in uric acid homeostasis as an efflux machinery, being expressed in the proximal renal tubules and the intestine. This study aimed to identify novel and functionally uncharacterized variants of the ABCG2 gene and to determine the frequency of known pathogenic variants in patients with primary hyperuricemia and gout.

Methods: A total of 549 patients were recruited from the RU Biobank, of whom 327 with primary gout and 222 with primary hyperuricemia. Individuals with secondary gout were excluded. Specific primers were designed to amplify all coding regions (15 exons; transcript ID: ENST00000650821), exon-intron boundaries, and two deep intronic variants (rs13120400 and rs7672194) of ABCG2. PCR amplification and Sanger sequencing were optimized and used to analyze the patient DNA (1). Identified ABCG2 variants were biochemically characterized using a mammalian cell-based expression system, followed by urate transport assays to assess transporter function.

Results: We detected a nonsynonymous variant p.Q141K with an allelic frequency of 0.22 (which is significantly higher than its minor allele frequency – MAF – in the European population: 0.094). This variant increases the risk of gout, while the common p.V12M variant appears to reduce the risk (MAF in patients: 0.026, MAF in European population: 0.061). We also identified one frameshift variant p.I63YfsTer54, two short deletions (p.K360del and p.F373del) and 14 rare or novel missense variants: p.M71V, p.G74D, p.M131I, p.R147W, p.T153M, p.I242T, p.R236X, p.F373C, p.T421A, p.T434M, p.S476P, p.A528T, p.S572R, and p.D620N (2,3). According to functional studies, nine of these variants lead to reduced or null transport function of ABCG2: p.M131I, p.R147W, p.T153M, p.I63YfsTer54, p.R236X, p.F373C, p.T434M, p.S476P, and p.S572R – all these variants were identified in pediatric patients with hyperuricemia and/or in patients with positive family history of hyperuricemia and gout.

Conclusion: Our findings confirm that the common p.Q141K variant and the majority of the identified rare ABCG2 variants negatively impact urate transport and significantly contribute to the risk of primary hyperuricemia and gout. Genetic screening for ABCG2 variants may be valuable in clinical practice, particularly in cases of early-onset or familial gout. Early identification and treatment of hyperuricemia in genetically predisposed individuals – including pediatric or adolescent patients with asymptomatic hyperuricemia – could delay the onset of gout and reduce the risk of related comorbidities.References: Rheumatology (Oxford). 2017 1; 56(11):1982-1992. Arthritis Res Ther. 2019 28;21(1):219. Int J Mol Sci. 2021 Feb 16;22(4):1935. Supported by the project Institute of Rheumatology 00023728, and by the grant from the Czech Republic Ministry of Health (NU22-01-00465), and BBMRI.cz (LM2023033).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/abcg2-variants-as-genetic-risk-factors-for-hyperuricemia-and-gout-focus-on-pediatric-and-familial-manifestations/