Background The urate transporters are one of the genetic determinants of serum uric acid concentrations. Common dysfunctional variants of ABCG2 are revealed to be a major cause of gout and hyperuricemia by decreasing urate excretion. In this study we describe the analysis of allelic variants in the ABCG2 in a cohort with primary gout.
Objectives The cohort was recruited in the Institute of Rheumatology, Prague. Gouty arthritis was diagnosed in 146 subjects (132 men, 14 women) according to the American college of rheumatology criteria 1977. Patients suffering from secondary gout and other purine metabolic disorders associated with pathological concentrations of serum uric acid were excluded.
Methods In each patient, the family history of gout, number of gouty attacks, the presence of tophi, the occurrence of associated diseases and therapy have been assessed. All 16 exons of ABCG2 were amplified using PCR, and sequenced directly.
Results In the ABCG2 gene, 19 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 introduction1. From the 12 exon variants detected, there were nine non-synonymous: p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T421A, p.T434M, p.S476P and p.D620N. Heterozygous p.V12M was detected in seven individuals. Heterozygous variants p.R147W, p.T153M, p.F373C, p.T421A, p.T434M and p.S476P were detected once, variant p.D620N twice. All these allelic variants were in silico predicted 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 gout patients presented with significantly higher minor allele frequency 0.24 (MAF), 57 heterozygotes/6 homozygotes, than in population of European origin (MAF=0.09) and world-wide population (MAF=0.12). In our cohort, the age of onset of gout had a normal distribution. Remarkably, in 75% of all individuals with early onset of gout between age 10–20 years, we detected allelic variant p.Q141K (in 6 out of 8 patients). In the age group 21–30 years, this allelic variant was detected in 42% of patients (8/19), and in the age group 61–70 years, just in 29% (13/29).
Conclusions Our results show that genetic factor ABCG2 should be considered as one of the strong common risks for gout. In summary, we revealed that allelic variants of ABCG2, especially dysfunctional variant p.Q141K, have a significant effect on earlier onset of gout.
Stiburkova B et al. 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.
Acknowledgements This study was supported by the grants from the Czech Republic Ministry of Health AZV 15–26693A.
Disclosure of Interest None declared