gms | German Medical Science

Background: It is estimated that genetic factors affect uric acid levels by about 40%. In terms of the development of gout, the most important urate transporter is ABCG2 (ATP-binding cassette sub-family G member 2), which is expressed in the proximal tubules of the kidneys and in the intestine.

Objectives: The aim of our study was to identify new genetic variants in ABCG2 and to determine the frequency of already known pathogenic variants in this gene in patients with primary hyperuricemia and gout.

Methods: We collected a cohort of 450 patients, of whom 278 had primary gout and 172 had primary hyperuricemia (subjects with secondary gout were excluded from the study). We designed specific primers for all coding regions (15 exons, transcript ID: ENST00000650821), exon-intron boundaries and two deep intronic variants (rs13120400 and rs7672194). Subsequently, we optimized the conditions of PCR amplification and Sanger sequencing and examined the patients’ DNA.

Results: In our cohort, we detected a nonsynonymous variant p.Q141K with an allelic frequency of 0.22 (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 two short deletions (p.K360del and p.F373del) and 14 rare 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 [1]. According to functional studies, eight of these variants lead to reduced transport function of ABCG2: p.M131I, p.R147W, p.T153M, p.R236X, p.F373C, p.T434M, p.S476P, and p.S572R [2].

Conclusion: Our data suggest that the common variant p.Q141K and most of the rare variants affect the transport function of the ABCG2 protein and are a significant risk factor for primary hyperuricemia and gout.