Background/Purpose: Common dysfunctional variants of ABCG2, a high-capacity urate transporter gene, that result in decreased urate excretion, are major causes of hyperuricemia and gout. However, the association of ABCG2 variants in pediatric-onset hyperuricemia and gout is unknown. In the present study, we analyzed the ABCG2 gene in a Czech hyperuricemia and gout cohort concentrating on patients with pediatric-onset before 18 years of age.

Methods: In total, 234 Caucasians suffering from hyperuricemia (N = 59) or primary gout (N = 175) were recruited, 31 with pediatric onset of the condition (18 hyperuricemia/13 gout); 115 normouricemic controls were used for comparison. Patients suffering from secondary gout and other purine metabolic disorders associated with pathological concentrations of serum uric acid were excluded. The pediatrics subjects were specifically screened for kidney and metabolic genetic disorders. We amplified, directly sequenced, and analyzed 15 ABCG2 exons¹. Chi-square goodness-of-fit test was used to compare minor allele frequencies, log-rank test to compare empirical distribution functions.

Results: The analysis of ABCG2 revealed two common nonsynonymous variants: rs2231137 (p.V12M) and rs2231142 (p.Q141K) and two rare nonsynonymous variants rs750972998 (p.K360del) and rs199854112 (p.T421A) in pediatric-onset subcohort. Seven of the 31 pediatric-onset patients were homozygous for p.Q141K and 11 were heterozygous. This makes the minor allele frequency (MAF) of p.Q141K 38.7 % compared to adult onset MAF = 21.2 % (OR = 2.4, P = 0.005), to normouricemic controls cohort MAF = 8.5 % (OR = 6.8, P < 0.0001) and Caucasian Central Europe population MAF = 9.4 % (OR = 5.7, P < 0.0001). One adolescent patient was compound heterozygous for p.Q141K and a rare variant p.K360del and one other patient was heterozygous for a rare p.T421A variant. Among the 31 pediatric-onset patients we have found 23 (74 %) that had affected family members (in 19 cases, 61 %, there were first degree relatives). This was more than twice than among adult onset individuals (31 %, P < 0.0001). Alternatively, while patients without family history of hyperuricemia/gout had median age of onset 47 years, patients with affected family members had median age of onset 28 years (P < 0.0001).

Conclusion:

Our data showed, for the first time, that ABCG2 dysfunction is strong independent risk in pediatric-onset of hyperuricemia and gout where other factors appearing in adulthood, such as alcohol consumption, diuretic use and increase in BMI, may further increase the risk of developing gout. The extremely high frequency of dysfunctional variants of the ABCG2 transporter among the patients with pediatric-onset of hyperuricemia and gout should be kept in mind during differential diagnostic procedures and probably also in therapeutic approach.

References

1. Stiburkova B, et al. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford). 2017 Nov 1;56(11):1982-1992.

Supported by the grants from the Czech Republic Ministry of Health: AZV 15-26693A, RVO 00023728 (Institute of Rheumatology), and RVO VFN64165.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/strong-impact-of-dysfunctional-variants-of-abcg2-on-hyperuricemia-and-gout-in-children-and-adolescents/