Elsevier

Clinica Chimica Acta

Volume 398, Issues 1–2, December 2008, Pages 140-144
Clinica Chimica Acta

T6092C polymorphism of SLC22A12 gene is associated with serum uric acid concentrations in Korean male subjects

https://doi.org/10.1016/j.cca.2008.09.008Get rights and content

Abstract

Background and object

It has been suggested that the SLC22A12 gene polymorphism may be involved in the mechanism of renal urate handling. The purpose of the current study was to identify the effect of the T6092C polymorphism of the SLC22A12 gene on serum uric acid concentrations in the Korean population.

Methods

We examined 196 healthy subjects (141 males and 55 females) in this study. Among the SLC22A12 gene polymorphism, the T6092C polymorphism in intron 4 at rs1529909 of the SLC22A12 gene was evaluated using denaturing high performance liquid chromatography analysis. Diverse clinical parameters of renal urate handling derived from fasting blood and urine samples, such as the serum uric acid concentration and the fractional excretion of uric acid (FEUA), were also assessed for identification of the relationship between genotypic variations. Statistical analysis was performed using the chi-square test, ANOVA test, and the Pearson correlation coefficient analysis to determine which indicators involved serum uric acid. And the significance of these indicators was then confirmed by multivariate regression analysis.

Results

The prevalence of the T6092C polymorphism (TT, TC, and CC) was 58.2%, 37.2%, and 4.6%, respectively. Only the concentration of serum uric acid and the FEUA in male subjects differed significantly among each genotype (p = 0.038 and p = 0.013, respectively). Serum uric acid concentrations in male subjects with the TT genotype were increased compared with those with the TC as well as the TC or CC genotypes (6.2 ± 1.2 vs. 5.7 ± 1.3, p = 0.039 and 6.2 ± 1.2 vs. 5.6 ± 1.3, p = 0.019, respectively), whereas there was no significant difference between CC genotype and TT genotype in serum uric acid (p = 0.066). No significant difference between clinical indicators and genotypes existed in females. The T6092C polymorphism of the SLC22A12 gene, serum creatinine, and the FEUA were significantly associated with the concentration of serum uric acid.

Conclusion

This study showed that the T6092C polymorphism of the SLC22A12 gene may be involved in renal urate handling and the concentration of serum uric acid, in male subjects.

Introduction

Uric acid is the end-product of either dietary or endogenous purine metabolism in humans and implicated in various medical conditions, including gout, cardiovascular diseases, and renal diseases [1], [2]. Serum uric acid concentrations primarily reflect the net balance between urate production through either exogenous or endogenous sources of purines and its excretion via other routes, such as the gastrointestinal tract and the kidneys. The circulating urate concentration is higher in humans than other mammals because of the inability to degrade uric acid by hepatic uric acid oxidase (uricase) into soluble allantoin in the peroxisome and the presence of a reabsoption mechanism of the filtered urate load in the proximal convoluted tubule of the kidneys [3], [4]. Approximately two-thirds of urate processed by daily purine metabolism is available for excretion by the urinary tract and the remaining one-third occurs in gastrointestinal secretions through the breakdown of urate by intestinal bacteria [5].

A complete understanding for the regulation of renal urate handling has not been clearly identified. Enomoto et al. recently identified a urate-anion exchanger or urate transporter in the human kidney, URAT1 (urate transporter 1) encoded by SLC22A12, known as a critical protein that regulates the human blood urate concentrations [6]. It has been established that URAT1 is mainly involved in the urate reabsorption and mutations in SLC22A12 gene encoding URAT1 cause renal hypouricemia. URAT1 is also implicated in a target molecule for either urate-increasing or urate-decreasing drugs that affected renal excretion of uric acid filtered in the glomerulus such as pyrazinamide, nicotinate, probenecid, and benzbromarone [6], [7].

It has been shown that SLC22A12 gene mutations are associated with the development of some medical conditions, including idiopathic renal hypouricemia and gout [6], [7], [8], [9]. The C850G mutation in SLC22A12 gene was found in 11 gouty patients whereas healthy volunteers did not have any mutation [8]. However, Taniguchi et al. found suppressing effect of G774A mutation in SLC22A12 on the development of gout [9]. In addition, the clinical significance of the SLC22A12 gene in other medical conditions has also been assessed in healthy subjects of some ethnic groups [10], [11], [12].

Vázquez-Mellado et al. investigated SLC22A12 gene analysis in patients with primary gout [8]. Their results showed 4 single nucleotide polymorphisms (SNPs) in exon 5 and 1 SNP in exon 4, but the remaining exons had no meaningful SNPs. Our study designed to identify SNPs in exon 5 of SLC22A12 gene. We could not find out any SNPs in exon 5. But we identified that intron 4 near from exon 5 had only one mutation of SLC22A12 gene, T6092C. In this study, we analyzed the association between the T6092C mutation in SLC22A12 gene and demographic characteristics, clinical indicators of renal uric acid excretion, and serum uric acid concentrations in healthy Korean population.

Section snippets

Subjects

The study population was consecutively recruited from unrelated healthy Korean subjects (141 males and 55 females) who visited a health promotion center. All of the subjects enrolled in this study agreed written informed consent. The protocol of this study was approved by the Institutional Review Board of Daegu Catholic University Medical Center. Information about the past medical history, current medications, and family history of the subjects were obtained from a medical interview of each

Frequency of alleles and genotypes in the SLC22A12 gene polymorphism

The frequencies of alleles and genotypes in the SLC22A12 gene analyzed in this study are shown in Table 1. Of the 196 subjects, the frequency of the T and C alleles was 76.8% and 23.2%, respectively. A similar frequency was identified with respect to gender (p = 0.356). One hundred fourteen subjects were identified to have the TT genotype (58.2%), 73 subjects had the TC genotype (37.2%), and 9 subjects had the CC genotype (4.6%). The differences in genotypic frequencies between males and females

Discussion

Serum uric acid concentration may be determined by overproduction of urate, impaired renal excretion, or often both of them, which was closely associated with a variety of dietary, genetic, and environmental causes. However, aberrant uric acid renal handling causing underexcretion has been known to a main pathogenic source in about 90% of subjects with persistent hyperuricemia. A multicompartmental model of urate transport in kidney may explain the complexity of uric acid renal handling, and

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