Elsevier

European Urology

Volume 44, Issue 1, July 2003, Pages 150-154
European Urology

Polymorphisms in the Vitamin D Receptor Gene and the Risk of Calcium Nephrolithiasis in Children

https://doi.org/10.1016/S0302-2838(03)00206-9Get rights and content

Abstract

Objective: Polymorphism in the Vitamin D Receptor (VDR) gene has recently been reported to be associated with calcium metabolism disorders. This study was conducted to investigate the association of VDR gene polymorphism with the risk of calcium nephrolithiasis.

Methods: We investigated the VDR ApaI, BsmI and TaqI polymorphisms, in relation to serum calcium, phosphate, intact parathyroid hormone and 1.25(OH)2D3 in 64 hypercalciuric stone-forming children and 90 healthy children. DNA was isolated from peripheral blood, and genotyping was performed with PCR-based methods.

Results: The frequency of ApaI AA genotype was significantly higher in the children with calcium nephrolithiais than the controls (χ2=9.5; p=0.008). The distribution of BsmI and TaqI genotypes in stone-forming patients was similar to those in the control group. There was a significant association between TaqI TT genotype and the strength of the family history. The patients with TT genotype were observed to have a 8 times more risk than patients with Tt/tt genotype for recurrent stone episodes (OR 8, 95%CI 1.61–39.6).

Conclusion: VDR genotype determination may provide a tool to identify individuals who are at a risk for calcium nephrolithiasis.

Introduction

Stone formation in the urinary tract is multifactorial. Metabolic alterations are found in 40% to 60% of children with renal stones; idiopathic hypercalciuria (IH) being the most frequent [1], [2]. The pathogenic role of IH in calcium nephrolithiasis has largely been documented. The supersaturation of urine with calcium salts depends on the urinary calcium concentration, that is, on the urine volume and the urinary calcium excretion rate [3]. Potential mechanisms for the pathogenesis of idiopathic hypercalciuria may involve: (1) an increase in intestinal calcium absorption (2) enhanced bone demineralization and/or decreased renal tubular calcium or phosphorous reabsorbtion [4], [5], [6], [7].

There is a considerable evidence that 1.25(OH)2D3 regulates target tissue biological response through some genomic events involving the interaction of the steroid hormone and the intracellular vitamin D receptor (VDR) [8]. It has been reported that the increased calcium absorption is mediated by an increase in the number of intestinal VDR in genetic hypercalciuric rats [9]. The VDR gene consists of nine exons and has several polymorphisms in intron 8 and exon 9, which are linkage disequilibrium with each other. Polymorphism in the VDR gene has been recently studied in calcium metabolism disorders and reported to be associated with population differences in bone density [10], [11], [12], [13]. The important role of the VDR in the stimulation of intestinal Ca absorption by 1.25(OH)2D3 makes its polymorphism a substantial target for the studies on the development of calcium-containing stones.

Relatively little is known about the genetic factors that mediate susceptibility to, and outcome of calcium nephrolithiasis. A positive family history is the single most important risk factor, after controlling for dietary habits [14]. Nephrolithiasis is familial in most of the patients and is most commonly associated with hypercalciuria. Furthermore urinary stone disease is one of the major common causes of chronic renal failure in our country with an incidence of 8% to 17.3% [15], [16]. The identification of genetic and environmental factors responsible for calcium nephrolithiasis will not only lead to a greater understanding of how the disease develops but also assists in the evaluation of high risk individuals.

The aim of this study is to investigate the association between VDR gene polymorphism and calcium nephrolithiasis.

Section snippets

Subjects

Sixty-four children (26 males, 38 girls) with calcium-containing stone disease with an age range of 2 to 14 years (mean 6.7±3.5 years, median 6 years) were enrolled in this study. The control group included 90 healthy children (47 males, 43 females) with an average age of 7.2±2.3 years. Inclusion criteria were as follows; urinary calcium excretion of more than 4 mg per kilogram of body weight per 24 hours in two consecutive urine collections; ultrasonographic or radiographic evidence of stone(s);

Results

Presenting symptoms and signs were: recurrent abdominal or flank pain in 38 (59.3%), dysuria in 25 (39.%) and hematuria in 32 (50%) (gross hematuria in 18 and microscopic hematuria in 14). Half of the patients exhibited more than one symptom/sign. Family history of urolithiasis was present in 31 (48.4%) of 64 children. Fourteen (21.8%) of the patients had recurrent stone disease.

Frequencies of ApaI, BsmI and Taq alleles and genotypes in the stone group and control are shown in Table 1. A

Discussion

The present study on children with calcium stone disease revealed significant difference in the prevalence of ApaI alleles compared with that of healthy controls. ApaI AA polymorphism was associated with 5.2 fold increased risk for stone disease. Nishijima et al. [19] reported that the rate of ApaI genotype was not different in the stone group and controls in Japanese population. However, they found that the incidence of TaqI Tt and tt genotypes were significantly higher in the high score group

Acknowledgements

Supported by the Gazi University Research Fund.

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    1

    Assistant Professor in Pediatric Nephrology.

    2

    Professor in Pediatric Nephrology.

    3

    PhD in Molecular Biology.

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