Gender-dependent associations of uric acid levels with a polymorphism in SLC2A9 in Han Chinese patients.

Hyperuricaemia predisposes to gout and is associated with increased risk of cardiovascular disease probably through a relationship with other cardiovascular risk factors, including metabolic syndrome, hypertension, and renal disease (1), and possibly through an independent effect (2). Several new loci have been identified to be associated with serum uric acid levels and gout in recent genome-wide association studies (GWAS), with the strongest signals detected for the solute carrier family 2, member 9 gene (SLC2A9) variants in various populations (3–5). The present study examined associations of eight single nucleotide polymorphisms (SNPs) in five of the most relevant candidate genes with uric acid levels in Chinese patients with increased cardiovascular risk requiring statin therapy. This study was conducted in Hong Kong Han Chinese patients with increased risk of coronary heart disease (CHD) (established CHD, familial hypercholesterolaemia,

member 9 gene (SLC2A9) variants in various populations (3)(4)(5). The present study examined associations of eight single nucleotide polymorphisms (SNPs) in five of the most relevant candidate genes with uric acid levels in Chinese patients with increased cardiovascular risk requiring statin therapy.
This study was conducted in Hong Kong Han Chinese patients with increased risk of coronary heart disease (CHD) (established CHD, familial hypercholesterolaemia, or CHD risk equivalent (6)), who had been involved in a pharmacogenetic study of the lipid response to rosuvastatin, as described previously (7). In brief, the most recent available plasma uric acid levels were obtained from 349 patients, including 137 with familial hypercholesterolaemia, 105 with diabetes, 186 with hypertension, and 133 with metabolic syndrome defined by the criteria for Asians (8). Eight key SNPs in five major candidate genes potentially related to uric acid balance identified from GWAS (5) were selected for analysis of associations with serum uric acid concentrations (Table 1). Genotyping was performed in the Genome Research Centre, University of Hong Kong, using the mass spectroscopy-based, high-throughput MassARRAY iPLEX™ platform (Sequenom, San Diego, CA, USA). The study was approved by the local Clinical Research Ethics Committee and all participants gave written informed consent. All SNPs genotyped were in Hardy-Weinberg equilibrium (χ 2 test p > 0.05). Among the eight SNPs examined in the analysis, the only significant finding was that the solute carrier SLC2A9 rs1014290 T>C C-allele was associated with lower serum uric acid levels (p ¼ 1.0 Â 10 À5 ), which were dependent on the association in women (Table 1). There was a significant association between the SLC2A9 rs1014290 T > C and uric acid levels in patients without hypertension (p ¼ 0.001) but not in patients with hypertension (p ¼ 0.057) (Figure 1). The rs12510549 in SLC2A9 or SNPs in other candidate genes were not significantly associated with uric acid levels.
The balance between urate reabsorption and secretion in the proximal renal tubules influences uric acid elimination and circulating uric acid concentrations. This study examined the associations between several renal transporter polymorphisms and plasma uric acid in Chinese patients with increased CHD risk receiving statin therapy. We found that the intronic SNP rs1014290 in SLC2A9 was significantly associated with reduced uric acid levels, which is consistent with previous GWAS findings showing that the strongest effect on serum uric acid concentrations was detected for several linked non-coding genetic variants of SLC2A9, including the rs1014290 polymorphism (3)(4)(5).
The SLC2A9 rs1014290 polymorphism had a more predominant effect on uric acid levels in females than males in the present study and in the GWAS in a range of genetic backgrounds including Caucasians, Blacks, and subjects from Mauritius (3,4,9). Although the exact mechanism of this gender-specific effect of SLC2A9 on uric acid levels is unclear, it has been shown that the expression of the urate transporter SLC22A12 was higher in male mice than in female mice and testosterone was shown to increase the transcription and expression of SLC22A12 in cell lines, suggesting a role for sex hormones in regulating the expression of SLC2A9 and other urate transporters (10). We also found that the association between SLC2A9 rs1014290 and uric acid level was more significant in patients without hypertension than those with hypertension, and this may be due to the influence of the disease itself and/or the use of antihypertensive drugs in patients with hypertension.
This study has several limitations. First, the lack of association of uric acid levels with the other SNPs examined in the study may be due to the small sample size. Second, the study participants were treated with multiple pharmacotherapy for the CHD risk factors, in particular statins, which may influence uric acid levels and/or their associations with genetic polymorphisms. In conclusion, the common SLC2A9 rs1014290 polymorphism was significantly associated with reduced uric acid levels in Chinese female patients with increased CHD risk.