Abstract
ObjectiveUsing European descent Czech populations, we performed a study of SLC2A9 and SLC22A12 genes previously identified as being associated with serum uric acid concentrations and gout. This is the first study of the impact of non-synonymous allelic variants on the function of GLUT9 except for patients suffering from renal hypouricemia type 2.MethodsThe cohort consisted of 250 individuals (150 controls, 54 nonspecific hyperuricemics and 46 primary gout and/or hyperuricemia subjects). We analyzed 13 exons of SLC2A9 (GLUT9 variant 1 and GLUT9 variant 2) and 10 exons of SLC22A12 by PCR amplification and sequenced directly. Allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. The functional studies were analyzed using the non-parametric Wilcoxon and Kruskall-Wallis tests; the association study used the Fisher exact test and linear regression approach.ResultsWe identified a total of 52 sequence variants (12 unpublished). Eight non-synonymous allelic variants were found only in SLC2A9: rs6820230, rs2276961, rs144196049, rs112404957, rs73225891, rs16890979, rs3733591 and rs2280205. None of these variants showed any significant difference in the expression of GLUT9 and in urate transport. In the association study, eight variants showed a possible association with hyperuricemia. However, seven of these were in introns and the one exon located variant, rs7932775, did not show a statistically significant association with serum uric acid concentration.ConclusionOur results did not confirm any effect of SLC22A12 and SLC2A9 variants on serum uric acid concentration. Our complex approach using association analysis together with functional and immunohistochemical characterization of non-synonymous allelic variants did not show any influence on expression, subcellular localization and urate uptake of GLUT9.
Highlights
The correlation between increased serum uric acid level and hypertension, cardiovascular disease, insulin resistance, metabolic syndrome and renal disorders has been recently described [1]–[3]
The importance of URAT1 and GLUT9 for regulating blood urate levels was confirmed by the finding of causal mutations in patients with idiopathic renal hypouricemia type 1 (OMIM #220150, RHUC1) and type 2 (OMIM #612076, RHUC2)
The secretion part of the transport of uric acid (UA) principally ensures the production of highly a variable gene ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) ABCG2
Summary
The correlation between increased serum uric acid level (hyperuricemia) and hypertension, cardiovascular disease, insulin resistance, metabolic syndrome and renal disorders has been recently described [1]–[3]. Hyperuricemia depends on the balance of endogenous production and the renal excretion of uric acid (UA). Population studies found the prevalence of the hyperuricemia in men at 24–29%, in women at 2.6–20% and rarely among children. UA is the end product of purine metabolism in humans. The absence of hepatic enzyme uricase in humans (and great apes) and effective renal urate reabsorption contribute to tenfold higher blood urate levels in humans compared to other mammals. About 75% of daily production of UA is excreted by the kidney while 25% is eliminated by the gastrointestinal tract. The ratio of excreted urate is only approximately 10%
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