We observed a strong sex-specific association between genetic variation within the SLC2A9 gene and uric acid concentrations. The finding was most pronounced in the population-based Bruneck Study and was replicated in severely obese and control individuals from Utah. This association was modified by BMI such that increasing BMI amplified effects of genetic variants on uric acid levels.
was recently identified by four independent genome-wide association studies to be strongly associated with uric acid levels (8
encodes a putative hexose transporter whose probable substrate is fructose (17
). Fructose intake has been described as an important contributor to uric acid levels and gout (18
), as the ADP generated during the phosphorylation of fructose is used for rapid production of uric acid (20
). Epidemiological data showed that increased total fructose intake correlated with increasing incidence of obesity, metabolic syndrome (21
), and gout (19
). Over the past decades, a general increase in uric acid levels was observed, and it was hypothesized that fructose-induced hyperuricemia might be in part responsible for the rise in metabolic syndrome (12
). The detection of genes that determine uric acid levels by influencing fructose metabolism would therefore be of interest. The actual mechanism of how genetic variation within SLC2A9
modulates uric acid levels has not been fully elucidated. One possibility would be an influence on the hepatic uptake of fructose and production of uric acid. On the other hand, SLC2A9
variants were associated with low fractional excretion of uric acid in various population samples, and experiments in Xenopus laevis
oocytes showed that SLC2A9
has not only fructose but also strong uric acid transport activity (11
It is important to note that we did not find an association between the genetic variants within the SLC2A9
gene and prevalent or incident metabolic syndrome or type 2 diabetes. This finding is intriguing given the pronounced association between the genetic variants and uric acid levels and the strong association of uric acid levels and these diseases in our study and in earlier studies. This may by explained, on the one hand, by lack of power: the variance in serum uric acid levels related to the genotypes investigated in population-based studies was about 1.2% in men and 6% in women (10
), and the fraction of these two diseases explained by uric acid levels was also small. On the other hand, the possibility that uric acid level is a surrogate marker of the disease without being in the causal pathway cannot be ruled out. However, recent studies in rats showed that fructose-induced metabolic syndrome is partially prevented by lowering uric acid levels and that the reduction in endothelial nitric oxide bioavailability caused by uric acid may be a mechanism for insulin resistance and hypertension (23
). A proof of a causal association of uric acid with disease end points might be possible by the application of a Mendelian randomization approach. However, this proof will probably require examination of several thousand individuals. Homozygotes of the wild type and of the rare allele differ in uric acid levels by 0.64–0.81 mg/dl, which corresponds to 11–13% of the mean levels. Based on the findings in earlier studies, such a difference in uric acid levels would change the rate of cardiovascular events by 1%.
A recent study with a systematic investigation of sex-specific differences of literature-reported genetic effects on various phenotypes documented that only one of 432 sex difference claims was consistently replicated in at least two other studies (24
). The association of genetic variants within SCL2A9
with uric acid levels clearly adds to this list, as much stronger associations were found in women than in men in five population samples in previous studies (10
) and in three population samples in this study. How obesity modulates the association between SLC2A9
variants and uric acid levels remains to be determined. It could be related to the higher fructose intake in obese subjects (22
) and a different saturation capacity of fructose transport depending on the genotype.
In summary, our study shows a strong association of genetic variants within the SLC2A9 gene and uric acid levels that is modified by sex and BMI.