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