B. Stiburkova 1,3, K. Pavelcova 1,2, M. Pavlikova 1, P. Ješina 3, K. Pavelka 1
1 Institute of Rheumatology, Prague, Czech Republic ² Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, Czech Republic ³ Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Background: ABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate under-excretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age.
Method: The cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31; 17 hyperuricemia/14 gout); 115 normouricemic controls were used for comparison. To explore the cause of hyperuricemia and gout, we performed a detailed metabolic investigation. The biochemical tests were performed using morning urine samples; 24-hour urine collections were not available. Patients suffering from secondary gout and other purine metabolic disorders associated with pathological concentrations of serum uric acid (such as the reduced activity of hypoxanthine-guanine phosphoribosyl-transferase and superactivity of phosphoribosyl pyrophosphate synthetase 1, i.e., resulting in increased excretion of xanthine and hypoxanthine in urine) were excluded. Pediatric subjects were specifically screened for kidney disorders (Fanconi syndrome and uromodulin-associated disorders) and for metabolic genetic disorders (glycogen storage disease, hereditary fructose intolerance, and mitochondrial disorders). We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions.
Results: Of the 31 pediatric-onset subjects, 19 non-consanguinity patients had at least of one non-synonymous allelic variant in the coding region of the ABCG2 gene. In the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P < 0.0001), and to the Central Europe Caucasian population MAF 9.4% (OR = 5.7, P < 0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Among the pediatric-onset patients we found that 23 (74%) had affected family members (in 19 cases, 61% were first degree relatives). This was more than twice that seen in the adult-onset group (31%, P < 0.0001). The trend was even stronger for hyperuricemic patients (82%) compared to (62%) for adolescent-onset gout patients. Alternatively, while patients without a family history of hyperuricemia/gout had a median onset age of 47 years, patients with affected family members had a median onset age of 28 years (P < 0.0001).
Conclusion: Our results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.