Influence of functional variants of the XDH gene on serum urate levels and the risk of gout

Abstract

Introduction. Xanthine oxidoreductase is an essential enzyme in the final stages of purine metabolism because it catalyzes the conversion of hypoxanthine to xanthine and then to uric acid (urate). Hyperuricemia is the primary risk factor for gout, an inflammatory disease involving the deposition of monosodium urate crystals in the joints. Previous studies have suggested that genetic variants in the XDH gene, which encodes this enzyme, may influence its expression and activity, thereby modifying gout risk.

Objectives. To evaluate the association of two functional variants of the XDH gene (rs17323225 and rs17011368) with gout susceptibility and their relationship with serum urate levels in a Mexican population cohort.

Methods. We included 41 patients with a clinical diagnosis of gout who were seen at the Instituto Nacional de Rehabilitación in Mexico City and 40 sex-matched healthy controls. Genotyping of the two variants was performed by real-time PCR. Serum glucose, cholesterol, triglyceride, and urate levels were determined using standard colorimetric methods. Genotypic frequencies and their association with gout were analyzed by logistic regression, as well as their correlation with urate levels.

Results. Patients with gout had significantly higher serum urate concentrations (8.0 ± 2.69 vs. 5.82 ± 2.63 mg/dL, p = 0.0004) and triglyceride levels (168.9 ± 56.2 vs. 132.6 ± 60.7 mg/dL, p = 0.007) than the control group. The rs17323225 variant exhibited a higher frequency of the homozygous TT genotype in gout patients, which was associated with a significant increase in disease risk (OR = 3.69, 95% CI = 1.06 - 12.8, p = 0.04). In addition, individuals with the TT genotype had significantly higher serum urate concentrations than those with the CC genotype (10.2 [95% CI, 3.7] vs 5.53 [95% CI, 1.3] mg/dL; p < 0.0001). Similarly, CT heterozygotes showed higher serum urate levels than CC genotype carriers (8.27 [RIC 1.5] vs. 5.53 [RIC 1.3] mg/dL, p = 0.012). There were no significant differences in other biochemical parameters (Figure 1).

Conclusions. Our results suggest that the rs17323225 variant of the XDH gene, specifically the TT genotype, is associated with higher urate levels and an increased risk of gout development.