Absence of <i>SLC22A12/URAT1</i> Gene Mutations in Patients with Primary Gout

Torres, Rosa J.; Miguel, Eugenio de; Bailén, Rebeca; Puig, Juan

doi:10.3899/jrheum.120451

Cited by 5 publications

(5 citation statements)

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“…The URAT1 nonfunctional variants (R90H and W258X) were not observed in any gout cases (n = 1,993), while R90H heterozygotes (G/A), W258X heterozygotes (G/A) and W258X homozygotes (A/A) were observed in 22, 150 and 2 subjects, respectively, among 2,499 control subjects ( P = 8.3 × 10 −46 ; Table 1 ). This result is compatible with previous studies 16 17 , and indicates that these URAT1 variants are protective factors of gout.…”

Section: Resultssupporting

confidence: 93%

“…Consistent with previous reports (on 77 Spanish 16 and 185 Japanese 17 gout patients, respectively), no URAT1 nonfunctional variants (R90H or W258X) were found even in our large number of gout patients (n = 1,993). Our results indicate that these URAT1 variants prevent the development of gout by the large-scale case-control study (case = 1,993 and control = 2,499).…”

Section: Discussionsupporting

confidence: 93%

“…Previous in vitro functional studies showed that R90H variant diminishes the urate transport activity of URAT1 15 as the other common variant, W258X 14 . It has been also reported that nonfunctional variants in URAT1 were not detected in 77 Spanish gout patients 16 , and W258X in URAT1 suppressed the development of gout 17 . However, to our knowledge, no large-scale case-control study has evaluated the relationship between gout/hyperuricemia and both variants (R90H and W258X).…”

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confidence: 92%

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The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression

Sakiyama

Shimizu

Nakashima

et al. 2016

Sci Rep

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Urate transporter 1 (URAT1/SLC22A12), a urate transporter gene, is a causative gene for renal hypouricemia type 1. Among several reported nonsynonymous URAT1 variants, R90H (rs121907896) and W258X (rs121907892) are frequent causative mutations for renal hypouricemia. However, no case-control study has evaluated the relationship between gout and these two variants. Additionally, the effect size of these two variants on serum uric acid (SUA) levels remains to be clarified. Here, 1,993 primary gout patients and 4,902 health examination participants (3,305 males and 1,597 females) were genotyped with R90H and W258X. These URAT1 variants were not observed in any gout cases, while 174 subjects had the URAT1 variant in 2,499 health examination participants, respectively (P = 8.3 × 10−46). Moreover, in 4,902 health examination participants, the URAT1 nonfunctional variants significantly reduce the risk of hyperuricemia (P = 6.7 × 10−19; risk ratio = 0.036 in males). Males, having 1 or 2 nonfunctional variants of URAT1, show a marked decrease of 2.19 or 5.42 mg/dl SUA, respectively. Similarly, females, having 1 or 2 nonfunctional variants, also evidence a decrease of 1.08 or 3.89 mg/dl SUA, respectively. We show that URAT1 nonfunctional variants are protective genetic factors for gout/hyperuricemia, and also demonstrated the sex-dependent effect size of these URAT1 variants on SUA (P for interaction = 1.5 × 10−12).

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 92%

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The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression

Sakiyama

Shimizu

Nakashima

et al. 2016

Sci Rep

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“…However, there was no statistically significant change in serum UA concentrations in mutant allele carriers. Collectively, no study has confirmed refuted URAT1 mutations in patient with gout and it is uncertain whether an enhanced tubular reabsorption of urate may cause hyperuricemia [35] , [36] .…”

Section: Discussionmentioning

confidence: 99%

Complex Analysis of Urate Transporters SLC2A9, SLC22A12 and Functional Characterization of Non-Synonymous Allelic Variants of GLUT9 in the Czech Population: No Evidence of Effect on Hyperuricemia and Gout

et al. 2014

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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.

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“…For subjects with no risk alleles, the crude prevalence of gout was 0.25 increasing to 52.48 for those with six risk alleles, representing a 208-fold increase. The finding of a significant correlation between the genetic risk score and both sUA and the prevalence of gout can best be interpreted as an indication that certain SNPs mark differences in the handling of urate in the kidney 35,36 . Characterization of patients' genotypes could thus help identify individuals at risk of gout, such as those with metabolic syndrome or cardiovascular diseases, and may help guide clinical decisions, particularly when considering drugs known to increase the levels of serum uric acid.…”

Section: Genetics Of Goutmentioning

confidence: 97%

Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease

Pérez-Ruiz

Becker

2015

Current Medical Research and Opinion

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Hyperuricemia and gout are independent risk factors associated with the development of hypertension, metabolic syndrome, vascular damage, and renal disease. Whether these risk factors are causally related to these important chronic co-morbidities remains uncertain, but inflammation may provide a mechanistic explanation. Hyperuricemia and gout negatively affect vascular function by exerting pro-oxidant effects and by decreasing nitric oxide bioavailability, thus inducing inflammation and endothelial dysfunction, which may promote hypertension, metabolic syndrome, and cardiovascular (CV) disease. This paper presents and discusses current understanding of the diverse influences promoting hyperuricemia and gout and the basis of acute and chronic hyperuricemia/gout-related inflammation. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.

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Absence of SLC22A12/URAT1 Gene Mutations in Patients with Primary Gout

Cited by 5 publications

References 10 publications

The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression

The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression

Complex Analysis of Urate Transporters SLC2A9, SLC22A12 and Functional Characterization of Non-Synonymous Allelic Variants of GLUT9 in the Czech Population: No Evidence of Effect on Hyperuricemia and Gout

Inflammation: a possible mechanism for a causative role of hyperuricemia/gout in cardiovascular disease

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