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Exp. Biol. Med. 2008;233:1608-1614
doi:10.3181/0803-RM-110
© 2008 Society for Experimental Biology and Medicine

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Association of Genetic Polymorphisms in Vitamin D Receptor Gene and Susceptibility to Sporadic Prostate Cancer

Ilke Hacer Onen*, Abdullah Ekmekci*1, Muzaffer Eroglu{dagger}, Ece Konac*, Suleyman Yesil{ddagger} and Hasan Biri{ddagger}

* Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, 06500, Ankara, Turkey; {dagger} Department of Urology, Faculty of Medicine, Abant Izzet Baysal University, Golkoy, 14280, Bolu, Turkey; and {ddagger} Department of Urology, Faculty of Medicine, Gazi University, Besevler, 06500, Ankara, Turkey

1 Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, 06500, Ankara, Turkey. E-mail: ilkeonen{at}gazi.edu.tr and aekmekci{at}yahoo.com


   Abstract
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Genetic and environmental factors are involved in prostate cancer (PCa) etiology. Single nucleotide polymorphisms (SNPs) may contribute to the PCa pathogenesis. The goal of this study is to determine the role of vitamin D receptor (VDR) gene polymorphisms and haplotypes in the development and progression of sporadic PCa. One hundred and thirty-three PCa patients and 157 age-matched healthy controls were genotyped for the Apa I (rs7975232), Bsm I (rs1544410) and Taq I (rs731236) polymorphisms in VDR gene by using polymerase chain reaction-restriction fragment length polymorphism. An association was observed between the Apa I polymorphism and PCa predisposition (P = 0.03). When compared with AA genotype, there was a highly notable difference in the frequencies of the Aa (P = 0.02), aa (P = 0.026) and Apa I ‘‘a’’ allele carriers (Aa + aa) (P = 0.009) genotypes. Furthermore, we found a statistical difference in the allele frequencies of the Apa I polymorphism between the sporadic PCa patients and control subjects (P = 0.013). The genotype distribution for the Bsm I and Taq I polymorphisms were similar between cases and controls (P > 0.05). No clinically significant relationship was found between the three-locus haplotypes and development of sporadic PCa. The genotype frequencies for the three polymorphisms of the VDR gene within subgroups of PCa (defined by tumor stage, Gleason score, PSA levels) were also analyzed, but no statistically noteworthy difference was observed (P > 0.05). As far as we know, this is the first study which investigates the relationship between VDR genotypes and sporadic PCa in the Turkish population. Our findings suggest that the VDR ApaI (rs7975232) polymorphism may play a role in the development of sporadic PCa.

Keywords: VDR gene, polymorphism, SNP, prostate cancer


   Introduction
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Prostate cancer (PCa) is one of the most commonly diagnosed forms of cancer among men in industrialized countries (1, 2). It is believed that many factors such as age, ethnicity, family history, diet, environment and genetic predisposition contribute to the etiology of this disorder (3–5). The risk of development of PCa varies among countries and ethnic groups. PCa incidence and mortality rates in Asian countries are much lower than those observed in western populations (5, 6). However, in general PCa incidence rates are rising rapidly in most countries, including low-risk populations (5, 7). The reasons for the ethnic and geographic variations in the incidence of, and mortality from, prostate cancer could be polymorphisms of genes associated with androgen secretion and metabolism (8, 9).

Vitamin D plays a prominent role in control of bone and calcium metabolism (10). Moreover, it is involved in a variety of biological processes including immune response metastasis, angiogenesis and apoptosis (11). In target cells, the biological action of 1 alpha, 25 dihydroxyvitamin D3 [1,25(OH)2D3]—active form of the vitamin D—is mostly mediated through the interaction of its receptor (VDR) (12). Then, this complex binds the retinoid X receptor to form a heterodimer. The heterodimer is responsible for the regulation of the other transcriptions of genes which result in cell cycle arrest in G1/S, apoptosis and differentiation (13). Chemopreventive effects of 1,25(OH)2D3 were shown in animal models of colon (14), gastrointestinal (15) and skin (16) cancer. It was also shown, in vitro, that 1,25(OH)2D3 has notable antiproliferative effects on malignant cells of prostate (17), breast (18), and colon (19) cell lines. Furthermore, Corder et al. (20) revealed a correlation between low 1,25(OH)2D3 blood levels and prostate cancer predisposition.

The vitamin D receptor gene is a member of the nuclear receptor family and expressed in over 30 different cell types and located on chromosome 12q12–14 (21, 22). VDR gene is highly polymorphic and allele frequencies are highly variable among different races and ethnic groups (23). To date, several polymorphisms at the 3' end of the VDR gene have been described using different restriction enzymes such as ApaI (24), BsmI (25), TaqI (26), Tru9I (27), and EcoRV (25). BsmI (rs1544410) and ApaI (rs7975232) (both in intron 8), and TaqI (rs731236) (in exon 9) are the most widely studied polymorphisms in linkage disequilibrium. TaqI polymorphism is located at codon 352, and T->C alteration (ATT to ATC) does not result in amino acid sequence change (26).

Although it is not known how these polymorphisms affect the VDR protein levels and functions, it is thought that 3' untranslated (UTR) sequence variances may affect the mRNA stability and protein translation efficiency (23).

The aim of this study is to investigate the association between the VDR polymorphisms and haplotypes and the development and progression of sporadic PCa in a specific Caucasian (Turkish) population.


   Materials and Methods
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Study Population.
The study group consisted of 157 controls and 133 newly diagnosed sporadic PCa cases, recruited from the Departments of Urology of the Gazi University and Abant Izzet Baysal University between 2003 and 2006. The study populations were Caucasian. Cases were classified according to the 2002 tumor-lymph nodes-metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) (28) and pathological grades (29). Clinical characteristics of the cases such as prostate specific antigen (PSA) at the time of diagnosis, tumour node metastasis (TNM) stage, tumour grade, as well as age at diagnosis and family history were obtained from medical records. All patients reported that there was no history of PCa in their first and second degree relatives. This information was recorded in form of a pedigree. The control group underwent clinical urologic examination which included digital rectal examination (DRE), transrectal ultrasound of the prostate (TRUS), residual urine volume, measurement of serum PSA and physical check-up. Any samples with abnormal DRE, suspicious lesion detected by TRUS, elevated serum levels of PSA ≥ 4 ng/ml were excluded from the control group. In addition, control subjects who had family history of cancer or a previous diagnosis of cancer were excluded from the study. Written informed consent was obtained from all cases and controls. The study was approved by the Ethical Committee of the Faculty of Medicine, Gazi University (Ankara, Turkey). Pathologic grades were determined according to the Gleason pattern and classified into (6 or lower), (7), or (8 or higher). Serum PSA levels were categorized into three groups: <10, 10–20 and >20 ng/ml. The clinical stages at the time of diagnosis were classified into Group I (cT1a–cT1c), Group II (cT2a–cT2c) and Group III (cT3a–cT4). Clinical profiles of the subjects are given in Table 1.

Genotyping.
Genomic DNA was extracted from peripheral blood lymphocytes using a commercially available DNA extraction kit (Heliosis®, Metis Biotechnology). Polymorphic sites in VDR (BsmI A/G, rs1544410), (ApaI A/C rs7975232), (TaqI C/T, rs731236), were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Primer sequences used for the amplification of a 191 bp fragment containing the BsmI polymorphic site in intron 8 and PCR conditions were the same as described in Sosa et al. (30). The PCR products were digested by BsmI (Roche Diagnostics GmbH, Mannheim, Germany) restriction enzyme at 65°C overnight. Digested PCR products with B allele remained uncut (191 bp) whereas those with b allele generated two fragments (115 bp and 76 bp).

The ApaI and TaqI polymorphisms were identified as reported by Ozkaya et al. (31). The 490-bp fragment generated by PCR was digested with the restriction endonucleases TaqI (MBI Fermentas, Lithuania) and ApaI (MBI Fermentas, Lithuania) at 65°C and 37°C respectively. Amplicons were digested with the restriction enzyme TaqI to yield a 490 bp fragment for the T allele, 290 and 200 bp for the t alleles. After digestion with ApaI, same PCR product was cut into 280 and 210 bp fragments in the presence of a allele, whereas A allele was undigested (490 bp). The PCR products and the restriction fragments were separated in 2% agarose gel stained with ethidium bromide, and were visualized by Logic 100 gel image system (Kodak, USA).

Analyzed VDR polymorphisms used to detect the base changes are shown in Table 2 (Methodical Nomenclature Recommended by Human Genome Variation Society, www.hgvs.org).

Statistical Analysis.
The observed genotype frequencies were used to test for Hardy-Weinberg equilibrium (HWE) and the {chi}2 test. The association between VDR genotypes defined by BsmI, ApaI, TaqI polymorphisms and prostate cancer was determined by analysis of Pearson chi square ({chi}2). The relationship between the genotype distribution and the clinicopathological parameters such as PSA levels, GS or tumor stage was analyzed using Pearson chi square ({chi}2) and Fisher’s exact probability tests. Crude odds ratios (ORs) were reported with 95% confidence intervals (CI). Differences between groups were considered statistically significant if P < 0.05. Statistical analysis was performed using SPSS version 15.0. The Linkage Disequilibrium (LD) values for the three pairs of SNPs have been calculated using Haploview Version 4.0 (Website: http://www.broad.mit.edu/mpg/haploview). One haplotype block was identified (32). Two different software, both of which were based on the expectation maximisation (EM) algorithm, were used for the estimation of the haplotype frequencies: Arlequin (version 3.1) (33) and SNPStats (34). Odds ratios (ORs) were calculated by {chi}2 test in comparison with the most common homozygote genotype as well as haplotype observed in studied population. The statistical power was calculated using the software QUAN-TO 1.2 (Website: http://hydra.usc.edu/gxe) (35). For the less frequent alleles (39.5% for BsmI, 39.8% for TaqI and 37.9% for ApaI) with P = 0.05, the study had a power >80 for all polymorphisms (OR = 2.0; mode of inheritance: log-additive).


   Results
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The observed control genotype frequencies of the two VDR polymorphisms, with the exception of the BsmI (rs1544410) polymorphism ({chi}2 < 4.06, P = 0.04), did not differ from those expected from Hardy-Weinberg equilibrium ({chi}2 < 0.14, P = 0.71 for the ApaI (rs7975232) and {chi}2 < 0.01, P = 0.99 for the TaqI (rs731236)). The genotype distribution in the cases was in Hardy-Weinberg equilibrium ({chi}2 < 0.26, P = 0.61 for the BsmI and {chi}2 < 0.05, P = 0.82 for the ApaI, {chi}2 < 0.01, P = 0.91 for the TaqI). Genotype distributions and allele frequencies of three VDR polymorphisms are displayed in Table 3. There was a statistical difference in the genotype distribution of the ApaI polymorphism among cases and controls (P = 0.03). Furthermore, compared with the AA genotype, the ORs for the Aa, aa and Aa + aa increased 1.88 (95% Cl, 1.10–3.20), 2.15 (95% Cl, 1.09–4.24) and 1.95 (95% Cl, 1.18–3.23) times, respectively. Therefore, a statistical difference was found in genotypic frequencies of the ApaI polymorphism between the sporadic PCa patients with Aa, aa, Aa + aa genotypes and those with AA genotype (P < 0.05) (Table 3). In addition, we found a statistical difference in the allele frequencies of the ApaI polymorphism between the sporadic PCa patients and control subjects (P = 0.013). When we compared the genotype distribution of the TaqI between PCa patients and controls, we found that the TT genotype was more frequent in cases (46.6%) than in controls (36.3%), although this difference was not statistically significant. The BsmI genotype distribution was similar in patients and healty controls (Table 3). We also analyzed the relation of the ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) genotypes to the clinicopathological parameters including PSA level, GS and tumor stage but observed no statistical differences. No significant association was found between allele frequencies of TaqI and BsmI of the VDR polymorphisms and prostate cancer. Pairwise LD coefficients (D' values) for three SNPs based on genotypes of 290 individuals of the case-control study were calculated and plotted (Fig. 1). Since we observed that all three SNPs were in LD, we continued with our haplotype study. We analyzed the BsmI, ApaI and TaqI separately as SNPs and also observed these three linked polymorphisms as haplotypes. The distributions of VDR haplotypes with estimation of ORs in PCa patients and controls are presented in Table 4.


   Discussion
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PCa is a heterogeneous disease (36). The prevalence of PCa varies dramatically among different geographic locations. Single nucleotide polymorphisms involved in steroid metabolism might be the cause of this difference (8, 9).

It is possible that various genes act together, in connection with other factors of the individual or the individual’s environment, to induce PCa development, prognosis and metastasis (37). Owing to the biological importance of Vitamin D function, polymorphisms of the VDR gene are the most widely studied (11, 26). Although the effects of the BsmI and ApaI polymorphisms on any splicing or transcription factor binding site are not presently known (38), it is possible that these polymorphisms might be linked to another genetic variation in the VDR gene itself or nearby polymorphic gene.

A study on the ApaI VDR polymorphism in Asian population did not observe an association between the frequency of any other particular genotypes and PCa (39). Two family-based association studies investigated the relationship between the VDR gene polymorphisms and PCa predisposition in Caucasian (40), African-American (40) and Asian (41) populations but no differences were found among cases and controls. Habuchi et al. (5) observed a significant difference between PCa and female controls. In a recent family-based study, Cicek et al. (42) found an association between the ApaI polymorphism and PCa. As far as we are concerned, the present study is the first one that demonstrates a relationship between the Aa, aa, ApaI ‘‘a’’ allele carriers (Aa + aa) genotypes of the ApaI (rs7975232) polymorphism and sporadic PCa in Caucasians. In our population-based case control study, we found that the PCa risk, in comparison to individuals with the AA genotype, increased in all individuals with either the Aa genotype (P = 0.02) or the aa genotype (P = 0.026) or ApaI ‘‘a’’ allele carriers (P = 0.009). These results show that, ApaI ‘‘a’’ allele of the VDR gene may be a risk factor for sporadic PCa. Furthermore, compared to the findings of Cicek et al. (42), we observed a significant increase in the distribution of the AA genotype frequency in our control group. Suzuki et al. (41) did not observe a relationship between clinicopathologic parameters and genotype distributions of the ApaI (rs7975232) polymorphism. Our results are similar to the findings of Suzuki et al. (41).

In this research, the genotype distributions and allele frequencies of the TaqI (rs731236) polymorphism were consistent with the findings of Cicek et al. (42). However, previous population-based case-control studies have been inconclusive regarding the association between the TaqI (rs731236) polymorphism and the PCa predisposition. Taylor et al. (2) indicated a positive association between the T alleles and PCa development. Correa-Cerro et al. (43) also observed that men with the Tt genotype had half the risk of PCa compared with those with the TT genotype. However, a meta-analysis which included 14 studies (44), and an additional five studies (39, 40, 45–47) observed no relationship between this polymorphism and PCa. Our findings did not support the previously reported association of T allele for the VDR gene with an increased risk of PCa (2, 43). Besides, Ma et al. (48) displayed the reduced risk observed for the tt genotype among men with lower 1,25(OH)2D3. Moreover, two researchers reported a note-worthy association between the TT genotype and advanced stage (3, 45) of PCa. However, these findings were not confirmed by Ma et al. (48), Blazer et al. (49) and Gsur et al. (50). Our results displayed no correlation between the TT genotype and the clinical variables as well.

The BsmI (rs1544410) genotype distribution indicated a narrow departure from Hardy-Weinberg equilibrium due to excess heterozygotes and low frequency of the BB genotype in controls. Furthermore, deviation from Hardy-Weinberg equilibrium was also found in control groups in three previous case-control studies (5, 51, 52). According to a meta-analysis, B allele frequency of the VDR was 41% in Caucasian and 14% in Asian control groups (44). Our genotype distributions are similar with those in the Caucasians studies by Ntais et al. (44). While a family-based study (40) found no difference between BsmI genotype and PCa, Suzuki et al. (41) showed a weak association between the BsmI genotype and PCa in subjects less than 70 years of age. Population-based case-control studies on PCa did not reveal a relation between any particular genotype of the BsmI and the risk of developing PCa (4, 5, 39, 51–53). Clinicopathological parameters were also examined in relation to BsmI genotype but no correlation was found between them (4, 51, 53) except in Huang et al. (39). Furthermore, Ma et al. (48) revealed that serum 1,25(OH)2D3 levels were significantly higher in men with BB genotypes.

A meta-analysis found no evidence indicating that any of the three alleles alone, was associated with PCa (44). Our findings did not differ from the mentioned study.

BAt haplotype was defined as protective for Caucasian populations in two investigations (2, 26). Moreover, Morrison et al. (26) showed that BAt haplotype had 140% more excessive receptor activity than baT haplotype. Cicek et al. (42) also showed that the distribution of a baT haplotype was slightly higher in patients with PCa than in the controls. In accordance with the findings of Cicek et al. (42), our study confirms that the most common haplotype in Caucasians is baT. Although, a statistical difference was observed haplotype frequency of BAt (OR: 0.64; 95% CI, 0.44–0.95; P = 0.025), this result was not clinically significant due to its negligible OR.

Consequently, our findings suggest that ApaI (rs7975232) polymorphism in the intron 8 of the VDR gene may confer susceptibility to sporadic PCa which may have important implications for understanding the pathogenesis of this cancer. With the support of our findings by successive research studies, ApaI (rs7975232) polymorphism may help detect individuals with higher risk of PCa. A limited number of patients were enrolled in our study which led us to work with a relatively small sample size. Therefore, further large-scale case-control studies on PCa, like Thomas et al. (54) and Eeeles et al. (55), are needed to better understand susceptibility to PCa. Confirmation of the importance of ApaI polymorphism in the development and progression of sporadic PCa and selection of the best treatment strategies in this respect could be possible through further studies based on larger sample sizes.


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  		Table 1. Clinical Characteristics of Prostate Cancer Patients and Controls

 


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  		Table 2. Polymorphisms in the VDR Gene and the Methods of Their Genotyping

 


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  		Table 3. Genotype and Allele Distribution of ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) Genotypes of VDR Gene in the Study Subjects

 


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  		Table 4. Distribution of VDR Haplotypes in Controls and Prostate Cancer Cases

 


Figure 1
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  		Figure 1. Locations and the linkage disequilibrium plot (obtained using Haploview) showing pairwise D' values (as percentage) between the three polymorphisms on VDR gene. LD blocks are framed in black and were classified according to the ‘‘solid spine’’ option (32). Each square plots the level of D' values between a pair of SNPs. The markers 1, 2, 3 are BsmI (rs1544410) A/G, ApaI (rs7975232) A/C, TaqI (rs731236) C/T, respectively.

 

   Footnotes
 
This study has been supported by the Gazi University Research Fund as a project with code number 01/2004–87.

This study was presented in the form of a poster to the Seventh National Congress on Prenatal Diagnosis and Medical Genetics, held on 17–20 May 2006 in Kayseri, Turkey.

Received for publication March 28, 2008. Accepted for publication August 21, 2008.


   References
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