Background/Purpose: Genetic variation in ABCG2 is a major risk factor for hyperuricemia and gout.  This gene encodes a high-capacity urate transporter expressed in the intestine, liver and renal tubule.  Intake of fructose-containing beverages is also associated with development of hyperuricaemia and gout.  A recent report has shown that variation in the other major genetic risk factor for gout, SLC2A9, influences serum urate (SU) and fractional excretion of uric acid (FEUA) responses to a fructose load. The aim of this study was to test the hypothesis that the ABCG2 gout risk allele 141K also promotes the hyperuricemic response to fructose loading.

Methods: Healthy volunteers (n=74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64g fructose solution.  Data were analyzed based on the presence or absence of the ABCG2 141K gout risk allele using a mixed models approach to repeated measures. 

Results: The 141K risk allele was present in 23 participants (31%). Overall, SU concentrations during the fructose load were similar in those with and without the 141K allele (P_SNP=0.15).  However, the presence of the 141K risk allele was associated with a smaller increase in SU following fructose intake (P_SNP<0.0001) (Figure 1A). Those with the 141K allele also had a smaller increase in serum glucose following the fructose load (P_SNP=0.002) (Figure 1B). Higher FEUA at baseline and throughout the fructose load was observed in those with the 141K risk allele (P_SNP<0.0001).  However, the change in FEUA in response to fructose was not different in those with and without the 141K risk allele (P_SNP=0.39).

Conclusion: In contrast to the predicted responses for a hyperuricemia/gout risk allele, the ABCG2 141K allele is associated with smaller increases in SU following a fructose load.  The FEUA data provide further evidence that the ABCG2 141K allele does not increase hyperuricemia/gout risk through direct effects on renal tubular uric acid transport.  Rather, the results suggest that ABCG2 variants may act through extra-renal metabolic pathways, which, in turn, influence SU levels and gout risk.

Figure 1: A. Change in SU. B. Change in serum glucose. Data are presented as mean (95% CI).  Dashed line represents 141K (risk) allele absent, solid line represents 141K (risk) allele present.