Background The urate transporter ABCG2 is one of the genetic determinants of serum uric acid concentrations1.
Objectives In the present study, we describe the identification and functional analysis of allelic variants in the ABCG2 gene, a physiologically important urate transporter whose dysfunction plays a major role in pathogenesis of gout, 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. We analyzed 15 exons of ABCG2 gene by PCR amplification and sequenced directly. The functional analysis of identified allelic variants is in process (HEK cells).
Results In the ABCG2 gene, 16 intronic sequence 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 introduction2.
From the nine exon variants detected, there were seven 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 seven individuals. Heterozygous variant p.R147W, p.T153M, p.F373C and p.D620N was detected once, variant p.D620N was detected twice also in heterozygous state. Variants p.R147W, p.T153M, p.F373C and p.T434M were in silico predicted using Polyphen, Sift and Provean program as a probably damaging. The p.Q141K, previously functionally characterized allelic variant with a strong effect on uric acid secretion impairment, was in cohort of hyperuricemic/gout patients presented with significantly higher 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).
Conclusions 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.
Stibůrková B, Pavlíková M, Sokolová J, Kožich V. Metabolic syndrome, alcohol consumption and genetic factors are associated with serum uric acid concentration. PLoS One. 2014 May 14;9(5):e97646.
Stiburkova B, Miyata H, Závada J, Tomčík M, Pavelka K, Storkanova G, Toyoda Y, Takada T, Suzuki H. 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.
Acknowledgement This study was supported by the grants from the Czech Republic Ministry of Health AZV 15–26693A.
Disclosure of Interest None declared