To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene.
We concluded that ABCG2 gene contributed to hyperuricemia but also gout, and that it was involved in the inflammation dysregulation via augmented IL-8 release in EC.
Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout.
These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.
Because ABCG2 dysfunctional diplotypes were commonly observed in both Caucasians (16.5%) and African-Americans (16.0%), the genotyping of the two ABCG2 dysfunctional variants is useful for evaluating individual differences in the ABCG2 dysfunction which affect the pharmacokinetics of substrate drugs and hyperuricemia risk in all three ethnic groups.
Key findings include the reporting of 28 urate-associated loci, the discovery that ABCG2 plays a central role on extra-renal uric acid excretion, the identification of genes associated with development of gout in the context of hyperuricaemia, recognition that ABCG2 variants influence allopurinol response, and the impact of HLA-B*5801 testing in reducing the prevalence of allopurinol hypersensitivity in high-risk populations.
Therefore, ABCG2 dysfunction originating from common genetic variants has a much stronger impact on the progression of hyperuricemia than other familiar risks.
Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years.
Together with high ABCG2 expression in extra-renal tissues, our data suggest that the 'overproduction type' in the current concept of hyperuricemia be renamed 'renal overload type', which consists of two subtypes-'extra-renal urate underexcretion' and genuine 'urate overproduction'-providing a new concept valuable for the treatment of hyperuricemia and gout.
This essentially includes our recent findings, as we serendipitously identified febuxostat, a well-used agent for hyperuricemia as a strong ABCG2 inhibitor, that possesses some promising potentials.
Plasma membrane expression of breast cancer resistance protein (BCRP), a uric acid efflux transporter, was decreased under hyperuricemia, though the total cellular expression of BCRP remained constant.
Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol.
Predictors of ULT misuse included the percentage of patients having gout (1-10%: OR=5.40, p=0.047) or receiving ULT (greater than 10-20%: OR=20.02, p=0.001)among patients seen in clinic, attendance of rheumatology conferences (OR=2.55, p=0.017), and having a close relative with hyperuricemia or gout (OR=2.45, p=0.026).
We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2.
The present results suggest that common dysfunctional variants of ABCG2 decrease extra-renal urate excretion including gut excretion and cause hyperuricemia.