Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI

Abstract

Objective: High serum uric acid levels lead to gout and have been reported to be associated with an increased risk of hypertension, obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Recently, the putative fructose transporter SLC2A9 was reported to influence uric acid levels. The aim of the present study was to examine the association of four single nucleotide polymorphisms within this gene with uric acid levels and to determine whether this association is modified by obesity.

Research design and methods: Four single nucleotide polymorphisms within SLC2A9 (rs6855911, rs7442295, rs6449213, and rs12510549) were genotyped in the population-based prospective Bruneck Study (n = 800) and in a case-control study from Utah including 1,038 subjects recruited for severe obesity and 831 control subjects.

Results: We observed highly significant associations between all four polymorphisms and uric acid levels in all study groups. Each copy of the minor allele decreased age- and sex-adjusted uric acid levels by 0.30-0.35 mg/dl on average, which translates to a relative decrease of 5-6% with P values ranging from 10(-9) to 10(-11) in the combined analysis. An extended adjustment for BMI, creatinine, gout medication, and alcohol intake improved P values to a range of 10(-14) to 10(-20). The association was more pronounced in women and the population-based Bruneck Study and was significantly modified by BMI, with stronger effect sizes in individuals with high BMI.

Conclusions: Genetic variants within SLC2A9 have significant effects on uric acid levels and are modified by sex and BMI.

Figure 1

Interaction plots describing the effect modification of BMI on the association of the four investigated SLC2A9 SNPs with uric acid levels. The x-axis displays the allelic status of the respective SNP; the y-axis corresponds to the predicted probability that an individual with the respective genotype exceeds the sex-specific median of uric acid levels given the specific BMI class. The quantitative interactions are represented as lines, with statistically significant differing slopes in all but one SNP (rs12510549). AA, Aa, and aa denote the three possible genotypes: wild-type, heterozygote carriers, and homozygotes for the minor allele, respectively.