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.
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.
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.
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.
The multidrug ATP-binding cassette, subfamily G, 2 (ABCG2) transporter was recently identified as an important human urate transporter, and a common mutation, a Gln to Lys substitution at position 141 (Q141K), was shown to cause hyperuricemia and gout.
To find candidate mutations in ABCG2, we performed a mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia and found six non-synonymous mutations.
Previous genome-wide association studies have found that the ABCG2 single nucleotide polymorphism (SNP) rs2231142 is an important genetic factor for increased uric acid (UA) levels, and the degree of association between rs2231142 and hyperuricemia is affected by both sex and ethnicity.
Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout.
Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.