Dataset Information

Urate transporter gene SLC22A12 polymorphisms associated with obesity and metabolic syndrome in Caucasians with hypertension.

ABSTRACT: Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects.Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825.In Caucasians, SLC22A12 SNPs were associated with the body mass index (BMI). rs11602903 was associated with BMI (p < 0.0001), waist circumference (p = 0.003), HDL cholesterol (p = 0.018) and the metabolic syndrome (p = 0.033), and accounted for 7% of the variation of BMI in Caucasians. In African Americans, SLC22A12 SNP rs11602903 was not associated with BMI, waist circumference, HDL cholesterol or triglycerides.The URAT1 gene SLC22A12 polymorphism may play a role in obesity and the metabolic syndrome in Caucasian hypertensive subjects.

SUBMITTER: Shafiu M

PROVIDER: S-EPMC3480975 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Urate transporter gene SLC22A12 polymorphisms associated with obesity and metabolic syndrome in Caucasians with hypertension.

Shafiu Mohamed M Johnson Richard J RJ Turner Stephen T ST Langaee Taimour T Gong Yan Y Chapman Arlene B AB Gums John G JG Johnson Julie A JA

Kidney & blood pressure research 20120608 6

<h4>Background/aims</h4>Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects.<h4>Methods</h4>Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825.<h4>Results</h4>In Caucasians, SLC22A12 SNPs were associated wit ...[more]

PMID: 22688828

Similar Datasets

Project description:INTRODUCTION: There is inconsistent association between urate transporters SLC22A11 (organic anion transporter 4 (OAT4)) and SLC22A12 (urate transporter 1 (URAT1)) and risk of gout. New Zealand (NZ) M?ori and Pacific Island people have higher serum urate and more severe gout than European people. The aim of this study was to test genetic variation across the SLC22A11/SLC22A12 locus for association with risk of gout in NZ sample sets. METHODS: A total of 12 single nucleotide polymorphism (SNP) variants in four haplotype blocks were genotyped using TaqMan® and Sequenom MassArray in 1003 gout cases and 1156 controls. All cases had gout according to the 1977 American Rheumatism Association criteria. Association analysis of single markers and haplotypes was performed using PLINK and Stata. RESULTS: A haplotype block 1 SNP (rs17299124) (upstream of SLC22A11) was associated with gout in less admixed Polynesian sample sets, but not European Caucasian (odds ratio; OR =?3.38, P?=?6.1?×?10-4; OR?=?0.91, P =?0.40, respectively) sample sets. A protective block 1 haplotype caused the rs17299124 association (OR?=?0.28, P?=?6.0?×?10-4). Within haplotype block 2 (SLC22A11) we could not replicate previous reports of association of rs2078267 with gout in European Caucasian (OR?=?0.98, P?=?0.82) sample sets, however this SNP was associated with gout in Polynesian (OR?=?1.51, P?=?0.022) sample sets. Within haplotype block 3 (including SLC22A12) analysis of haplotypes revealed a haplotype with trans-ancestral protective effects (OR?=?0.80, P?=?0.004), and a second haplotype conferring protection in less admixed Polynesian sample sets (OR?=?0.63, P?=?0.028) but risk in European Caucasian samples (OR?=?1.33, P?=?0.039). CONCLUSIONS: Our analysis provides evidence for multiple ancestral-specific effects across the SLC22A11/SLC22A12 locus that presumably influence the activity of OAT4 and URAT1 and risk of gout. Further fine mapping of the association signal is needed using trans-ancestral re-sequence data.

Project description:The 'Mendelian randomization' approach uses genotype as an instrumental variable to distinguish between causal and non-causal explanations of biomarker-disease associations. Classical methods for instrumental variable analysis are limited to linear or probit models without latent variables or missing data, rely on asymptotic approximations that are not valid for weak instruments and focus on estimation rather than hypothesis testing. We describe a Bayesian approach that overcomes these limitations, using the JAGS program to compute the log-likelihood ratio (lod score) between causal and non-causal explanations of a biomarker-disease association. To demonstrate the approach, we examined the relationship of plasma urate levels to metabolic syndrome in the ORCADES study of a Scottish population isolate, using genotype at six single-nucleotide polymorphisms in the urate transporter gene SLC2A9 as an instrumental variable. In models that allow for intra-individual variability in urate levels, the lod score favouring a non-causal over a causal explanation was 2.34. In models that do not allow for intra-individual variability, the weight of evidence against a causal explanation was weaker (lod score 1.38). We demonstrate the ability to test one of the key assumptions of instrumental variable analysis--that the effects of the instrument on outcome are mediated only through the intermediate variable--by constructing a test for residual effects of genotype on outcome, similar to the tests of 'overidentifying restrictions' developed for classical instrumental variable analysis. The Bayesian approach described here is flexible enough to deal with any instrumental variable problem, and does not rely on asymptotic approximations that may not be valid for weak instruments. The approach can easily be extended to combine information from different study designs. Statistical power calculations show that instrumental variable analysis with genetic instruments will typically require combining information from moderately large cohort and cross-sectional studies of biomarkers with information from very large genetic case-control studies.

Project description:Background and objective: Gout is a common form of inflammatory arthritis caused by the crystallization of uric acid. Previous studies have demonstrated that the genetic predisposition of gout varies in different ethnic populations. However the association study of genetic variants with gout remains unknown in the Vietnamese population. Our study aimed to assess the relationship between polymorphisms in ABCG2 and SLC22A12 and gout susceptibility in Vietnamese. Materials andmethods: Genomic DNA was extracted from blood of a total of 170 patients with gout and 351 healthy controls. We genotyped single nucleotide polymorphisms (SNPs): rs72552713, rs12505410 of the ABCG2 gene and rs11231825, rs7932775 of the SLC22A12 gene using polymerase chain reaction⁻restriction fragment length polymorphism (PCR⁻RFLP) and then confirmed 10% of randomly selected subjects by Sanger sequencing. Results: Three SNPs (rs72552713 and rs12505410 and rs11231825) were in accordance with Hardy⁻Weinberg Equilibrium (HWE) (p > 0.05) while rs7932775 was not (p < 0.05). For rs72552713, CT genotype was significantly different between gout patient and control groups (p < 0.001) and the T allele was associated with an increased risk of gout (OR = 21.19; 95% CI: 3.00⁻918.96; p < 0.001). Serum uric acid and hyperuricemia differed significantly between CC and CT genotype groups (p = 0.004 and 0.008, respectively). For rs11231825, a protective effect against gout risk was identified in the presence of the C allele when compared with the T allele (OR = 0.712; 95% CI: 0.526⁻0.964 p = 0.0302). In contrast, no significant difference of allele frequencies between gout patients and controls was detected for rs12505410 (p > 0.05). However, significant differences in serum uric acid and systolic blood pressure were obtained among gout patients. Conclusion: Our results suggest that ABCG2 rs72552713 and SLC22A12 rs11231825 are likely associated with gout in the Vietnamese population in which T allele may be a risk factor for gout susceptibility.

Project description:Chronic gouty arthritis, caused by a persistent increase in, and the deposition of, soluble uric acid (sUA), can induce pathological chondrocyte destruction; however, the effects of urate transport and intracellular sUA on chondrocyte functionality and viability are yet to be fully determined. Thus, the aim of the present study was to investigate the presence and functionality of a urate transport system in chondrocytes. The expression profiles of two primary urate reabsorptive transporters, glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), in human articular cartilage and chondrocyte cell lines were examined via western blotting, reverse transcription‑quantitative PCR, immunohistochemistry and immunofluorescence. Then, chondrocytes were incubated with exogenous sUA at increasing concentrations. Negative control assays were conducted via the specific knockdown of GLUT9 and URAT1 with lentiviral short hairpin (sh)RNAs, and by pretreatment with benzbromarone, a known inhibitor of the two transporters. Intracellular UA concentrations were measured using colorimetric assays. The expression levels of GLUT9 and URAT1 were determined in cartilage tissues and chondrocyte cell lines. Incubation of chondrocytes with sUA led to a concentration‑dependent increase in intracellular urate concentrations, which was inhibited by GLUT9 or URAT1 knockdown, or by benzbromarone pretreatment (27.13±2.70, 44.22±2.34 and 58.46±2.32% reduction, respectively). In particular, benzbromarone further decreased the already‑reduced intracellular UA concentrations in HC‑shGLUT9 and HC‑shURAT1 cells by 46.79±2.46 and 39.79±2.22%, respectively. Cells overexpressing GLUT9 and URAT1 were used as the positive cell control, which showed increased intracellular UA concentrations that could be reversed by treatment with benzbromarone. In conclusion, chondrocytes may possess an active UA transport system. GLUT9 and URAT1 functioned synergistically to transport UA into the chondrocyte cytoplasm, which was inhibited by specific gene knockdowns and drug‑induced inhibition. These results may be fundamental in the further investigation of the pathological changes to chondrocytes induced by sUA during gouty arthritis, and identified UA transport processes as potential targets for the early control of chronic gouty arthritis.

Dataset Information

Urate transporter gene SLC22A12 polymorphisms associated with obesity and metabolic syndrome in Caucasians with hypertension.

Publications

Urate transporter gene SLC22A12 polymorphisms associated with obesity and metabolic syndrome in Caucasians with hypertension.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets