Elsevier

Life Sciences

Volume 79, Issue 23, 2 November 2006, Pages 2234-2237
Life Sciences

Association between intronic SNP in urate-anion exchanger gene, SLC22A12, and serum uric acid levels in Japanese

https://doi.org/10.1016/j.lfs.2006.07.030Get rights and content

Abstract

Serum uric acid levels are maintained by urate synthesis and excretion. URAT1 (coded by SLC22CA12) was recently proposed to be the major absorptive urate transporter protein in the kidney regulating blood urate levels. Because genetic background is known to affect serum urate levels, we hypothesized that genetic variations in SLC22A12 may predispose humans to hyperuricemia and gout. We investigated rs893006 polymorphism (GG, GT and TT) in SLC22A12 in a total of 326 Japanese subjects. Differences in clinical characteristics among the genotype groups were tested by the analysis of variance (ANOVA). In male subjects, mean serum uric acid levels were significantly different among the three genotypes. Levels in the GG genotype subjects were the highest, followed by those with the GT and TT genotypes. However, no differences between the groups were seen in the distributions of creatinine, Fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, HDL cholesterol levels or BMI. A single nucleotide polymorphism (SNP) in the urate transporter gene SLC22CA12 was found to be associated with elevated serum uric acid levels among Japanese subjects. This SNP may be an independent genetic marker for predicting hyperuricemia.

Introduction

Uric acid is the final product of purine metabolism in humans. The higher serum levels of uric acid in humans when compared with other animals are partially due to the absence of urate oxidase, a hepatic enzyme that degrades uric acid, and partially due to the lower fractional excretion of uric acid from the kidney. Although higher serum urate levels have been suggested to be beneficial, as urate may act as a scavenger of biological oxidants (Ames et al., 1981), urate is also implicated in numerous disease processes, such as hypertension, coronary artery disease, gout and nephrolithiasis.

Uric acid in blood is saturated at 6.4–6.8 mg/dl under ambient conditions, with the upper limit of solubility at 7.0 mg/dl (420 μmol/l). Hyperuricemia is defined as serum uric acid concentrations of greater than 7.0 mg/dl, irrespective of gender and age, according to the guidelines of the Japanese Society of Gout and Nucleic Acid Metabolism (Japanese Society of Gout and Nucleic Acid Metabolism, 2002). Hyperuricemia may occur due to increased uric acid production, decreased uric acid excretion, or a combination of the two. In the general population, 80% to 90% of gout patients are underexcreters (Rott and Agudelo, 2003). It is thought that transporters for urate reabsorption and secretion may be present throughout the proximal tubules. The direction of net urate flux would thus depend on the number or activity of resorptive and secretory transporters present in the luminal and basolateral membranes, respectively.

A urate-anion exchanger or urate transporter in the human kidney, URAT1, was recently identified as the protein that regulates blood urate levels (Enomoto et al., 2002). This transporter was immunohistochemically detected in the epithelial cells of the proximal tubules, and exhibited properties such as inhibition by uricosuric and antiuricosuric agents, which is consistent with its physiological function. Moreover, patients with idiopathic renal hypouricemia have been found to have a homozygous nonsense mutation in SLC22A12, which encodes URAT1. We therefore hypothesized that genetic variations in SLC22A12 may predispose humans to hyperuricemia. Herein, we report that an SNP in an intron of SLC22A12 is associated with higher urate levels in Japanese subjects.

Section snippets

Subjects

A total of 326 subjects, who visited the General Health Check-up Center of Toranomon Hospital in May, 1995, were selected. Subjects consisted of 213 males and 113 females. The mean (SD) age of the study population was 49.4 (8.1) years in male and 50.4 (8.2) in female. Informed consent was obtained from all subjects. The present study was approved by the Ethical Committee of Kyorin University School of Health Sciences (Ethical Committee Approval Number 15-20).

Genotyping of SLC22A12 SNP

Genomic DNA was isolated from

Genotypes and metabolic characteristics in Japanese subjects

Of the SLC22A12 SNPs identified as of September 2002, rs893006, which has been detected in a high frequency, was investigated. The frequency of the G allele was 0.844 and that of the T allele was 0.156. Among the 326 subjects, 233 (71.5%) had the GG genotype, 84 (25.8%) had GT, 9 (2.7%) TT genotypes. The frequencies of three genotypes in males and females were at similar levels, and the genotype frequency was in agreement with the Hardy–Weinberg equilibrium.

The middle values of reference uric

Discussion

Hyperuricemia may result from uric acid overproduction, underexcretion or a combination of the two. A minority of overproducers have been identified to have defects in the enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT), the complete absence of which causes Lesch–Nyhan syndrome (LNS; Lesch and Nyhan, 1964), while partial deficiency causes Kelley–Seegmiller syndrome (KSS; Kelley et al., 1969). Accelerated purine synthesis as a consequence of phosphoribosyl pyrophosphate synthetase

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