Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge.
BACKGROUND
Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic 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 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele.


RESULTS
The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m².


CONCLUSIONS
In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk.


BACKGROUND
The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).
Nicola
N
Dalbeth
Meaghan E
ME
House
Gregory D
GD
Gamble
Bregina
B
Pool
Anne
A
Horne
Lauren
L
Purvis
Angela
A
Stewart
Marilyn
M
Merriman
Murray
M
Cadzow
Amanda
A
Phipps-Green
Tony R
TR
Merriman
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000483:Alleles; D001786:Blood Glucose; D005260:Female; D005632:Fructose / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006073:Gout / Q000235:genetics / Q000378:metabolism; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D012042:Registries; D012307:Risk Factors; D014527:Uric Acid / Q000032:analysis* / Q000378:metabolism*
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D009363:Neoplasm Proteins; D014527:Uric Acid; D005632:Fructose