The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH) D Serum Levels and Prostate Cancer among Jordanian Men

Abstract

cause of cancer death in men in the Western world. Vitamin D (1,25dihydroxy vitamin D) is linked to many
biological processes that influence oncogenesis but data on relations between its genetic variants and cancer
risk have been inconsistent. The aim of this study was to determine associations between a vitamin D genetic
polymorphism and 25-hydroxyvitamin D [25(OH)D] levels and prostate cancer. Materials and Methods: Genomic
DNA was extracted from 124 Jordanian prostate cancer patients and 100 healthy volunteers. Ethical approval
was granted from the ethical committee at Hashemite University and written consent was given by all patients.
PCR was used to amplify the vitamin D receptor Fok1 polymorphism fragment. 25(OH)D serum levels were
measured by competitive immunoassay. Results: All genotypes were in Hardy-Weinberg equilibrium. Genotype
frequency for Fok1 genotypes FF, Ff and ff was 30.7%, 61.3% and 8.06%, for prostate cancer patients, while
frequencies for the control group was 28.0%, 66.0% and 6.0%, respectively, with no significant differences.
Vitamin D serum level was significantly lower in prostate cancer patients (mean 7.7 ng/ml) compared to the control
group (21.8 ng/ml). No significant association was noted between 25(OH)D and VDR Fok1 gene polymorphism
among Jordanians overall, but significant associations were evident among prostate cancer patients (FF, Ff and
ff : 25(OH)D levels of 6.2, 8.2 and 9.9) and controls (19.0, 22.5 and 26.3, respectively). An inverse association
was noted between 25(OH)D serum level less than 10ng/ml and prostate cancer risk (OR 35.5 and 95% CI 14.3-
88.0). Conclusions: There is strong inverse association between 25(OH)D serum level less than 10ng/ml level
and prostate cancer risk

Full text

Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 2227
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.6.2227
The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH)D Levels and Prostate Cancer among Jordanian Men
Asian Pac J Cancer Prev, 16 (6), 2227-2230
Introduction
PCa is one of the most commonly diagnosed forms
of cancer among men in industrialized countries (Nwosu
et al., 2001), whose incidence rates are rising rapidly in
most countries including low-risk populations (Habuchi
et al., 2000). It is a health problem in developed countries
because of their greater proportion of elderly men. About
15% of male cancers are PCa in developed countries
compared to 4% of male cancers in developing countries
(Parkin et al., 2001). Prostate cancer incidence increases
with age and it is estimated that 80% of men would be
affected by the age of 80 years (Holund, 1980). In Jordan,
PCa is the sixth among Jordanian male cancer which
accounted for 7.9% of male cancers (www.moh.gov.jo).
Vitamin D (the sun-shine vitamin) plays a prominent
role in bone and calcium metabolism also has functions
in the immune system, central nervous system, epithelial
cells, and various endocrine processes (Haussler et al.,
1998). It has anticancer effects that are mediated through
the vitamin D receptor (Brown et al., 1999), It promote
1Medical Laboratory Department, Allied Health Sciences, 2Faculty of Medicine, Hashemite University, Zarqa, Jordan *For
correspondence: manar@hu.edu.jo
Abstract
Background: Prostate cancer (PCa) is one of the most commonly diagnosed neoplasms and the second leading
cause of cancer death in men in the Western world. Vitamin D (1,25dihydroxy vitamin D) is linked to many
biological processes that inuence oncogenesis but data on relations between its genetic variants and cancer
risk have been inconsistent. The aim of this study was to determine associations between a vitamin D genetic
polymorphism and 25-hydroxyvitamin D [25(OH)D] levels and prostate cancer. Materials and Methods: Genomic
DNA was extracted from 124 Jordanian prostate cancer patients and 100 healthy volunteers. Ethical approval
was granted from the ethical committee at Hashemite University and written consent was given by all patients.
PCR was used to amplify the vitamin D receptor Fok1 polymorphism fragment. 25(OH)D serum levels were
measured by competitive immunoassay. Results: All genotypes were in Hardy-Weinberg equilibrium. Genotype
frequency for Fok1 genotypes FF, Ff and ff was 30.7%, 61.3% and 8.06%, for prostate cancer patients, while
frequencies for the control group was 28.0%, 66.0% and 6.0%, respectively, with no signicant differences.
Vitamin D serum level was signicantly lower in prostate cancer patients (mean 7.7 ng/ml) compared to the control
group (21.8 ng/ml). No signicant association was noted between 25(OH)D and VDR Fok1 gene polymorphism
among Jordanians overall, but signicant associations were evident among prostate cancer patients (FF, Ff and
ff : 25(OH)D levels of 6.2, 8.2 and 9.9) and controls (19.0, 22.5 and 26.3, respectively). An inverse association
was noted between 25(OH)D serum level less than 10ng/ml and prostate cancer risk (OR 35.5 and 95% CI 14.3-
88.0). Conclusions: There is strong inverse association between 25(OH)D serum level less than 10ng/ml level
and prostate cancer risk.
Keywords: Prostate cancer - vitamin D - Fok1 polymorphism - Jordan
RESEARCH ARTICLE
The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH)
D Serum Levels and Prostate Cancer among Jordanian Men
Manar Fayiz Atoum1*, Dena AlKateeb1, Sameer Ahmed AlHaj Mahmoud2
cell differentiation, apoptosis, inhibition of cellular
proliferation, angiogenesis and tumor cell invasion (Holt
et al., 2009; Luong et al., 2010). VDR activation may
regulate directly or indirectly the expression of 100-1250
genes (Yu and Cantorna, 2011; Zhang and Ho, 2011).
Vitamin D exerts its biological effects through binding and
activating the intracellular VDR, which acts as a ligand-
dependent transcriptional factor in many types of tissues,
including the prostate (Miller et al., 1992).
VDR is expressed in over 30 different cell types and
located on chromosome 12q12-14 (Wu-Wong, 2007).
Consisting of 14 exons and spanning approximately 75
kb long (Crofts et al., 1998). VDR gene encompasses two
promoter regions, eight protein-coding exons (namely 2-9]
and six untranslated exons (1a-1f) (Baker et al., 1998).
Exons 2 and 3 of the VDR gene are involved in DNA
binding, and exons 7, 8, and 9 are involved in binding to
vitamin D (Hughes et al., 1988).
Polymorphisms of the VDR gene potentially affect
the receptor binding Of 1, 25dihydroxyvitamin D3, that
may modify vitamin D biological activity and confer

Manar Fayiz Atoum et al
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015
2228
susceptibility to prostate cancer (Yin et al., 2009). Oral
administration of active vitamin D metabolites delays the
recurrence of prostate cancer following primary therapy
(Gross et al., 1998). This indicates that active vitamin D
metabolites can be effective in slowing the progression
of prostate cancer risk.
VDR gene is highly polymorphic and its allele
frequencies are highly variable among different races
and ethnic groups. More than sixty VDR polymorphisms
have been discovered that are located in the promoter,
in and around exons 2-9 and in the 3’UTRregion (Peehl
et al., 1994). VDR gene variants that are studied include
a 5’ Fok1 site in exon 2 that alters the start codon (Li et
al., 1999). Correlation between low circulating levels
of 25(OH)D were associated with an increased risk of
subsequent earlier onset and more aggressive progression
of prostate cancer, especially before the age of 52 (Polek
and Weigel, 2002).
The aim of this study is to determine rs10735810 or
Fok1 polymorphism on exon 2 within VDR gene among
prostate cancer Jordanian males. This polymorphism
contain two potential translation initiation (ATG or
start) sites (Saijo et al., 1991). A polymorphism has
been described in the rst start codon which changes the
nucleotide sequence to ACG. The f allele contains both
ATGs, whereas the F allele has only the second ATG, and
thus predicts a shorter VDR protein (Ingles et al., 1998).
This study also determined vitamin D level among prostate
cancer patients and determine any association between
v25(OH) D level and VDRFok1gene polymorphism
among prostate cancer patients.
Materials and Methods
A total of 124 prostate cancer patients were recruited
from the urogenital cancer clinic at Al- Basheer Hospital/
Amman (2013-2014)that were histopathologically
diagnosed with prostate cancer by specialized pathologists.
One hundred age matched control volunteers with no
familial history of any cancer were recruited from the
Jordanian society. Ethical approval for this study was
received from the Institutional Review Board (IRB) at the
Hashemite University. Consent forms were signed by all
participants before interviewing and sample collection.
Plain tubes samples were centrifuged within two hours
of sample collection, Serum was separated and stored
at-60ºC for vitamin D determination. EDTA tubes were
used for DNA extraction with in 2-4 hours from collection.
Almost 500μl of serum aliquots were used to measure
serum 25(OH) D level using Elecsys vitamin D total assay
kit (Roche Diagnostics, Switzerland) by MODULAR
ANALYTICSE170 analyzer.
DNA samples were extracted using the Wizard
Genomic DNA Purication kit (Promega, USA). DNA
samples were amplied using the BIO RAD iCycler
with the specic primers that are complementary to Fok1
VDR gene
Forward 5’-ACTCTGGCTCTGACCGTG-3’ and
Reverse 5’-TCATAGCATTGAAGTGAAAGC. PCR was
conducted using Go Taq® Green Master Mix DNA, then
samples were amplied: Initial denaturation step at 94˚C
for 3 min, followed by 35 cycles of denaturation step at
94ºC for 90 sec then annealing step at 58ºC for 60s and
extension at 72ºC for 90s. Finally the refrigeration cycle
at 4ºC. Following amplication, SNPs FokI(rs2228570) in
VDR gene was detected by restriction enzyme digest using
the restriction endonuclease digestion (Jenna Bioscience,
Germany) at 37°C for two hours. All fragments then
visualized on 2% agarose gel electrophoresis. The
expected size of FokI (FF) genotype is159 bp, FokI (Ff)
genotype are159 bp+53 bp+106 bp and for FokI (ff)
genotype are 53 bp+106 bp.
Statistical analysis was performed using the Statistical
Package for Social Sciences (SPSS) version 20.Chi-
square test was used to evaluate case-control differences
for FokI genotype distribution among case and control
groups. T- test was used to evaluate the signicance of
difference of mean 25(OH)D levels between case and
control groups. The association between FokI different
genotypes and prostate cancer risk, vitamin D level and
FokI different genotypes were evaluated by calculating
the odd ratios (OR) using “Mantel Haenszel”method and
95% condence intervals (CI).
Results
The genotypes and allele frequencies of FokI VDR
gene polymorphism among prostate cancer and control
participants are shown in table (1). The genotypes are
in Hardy-Weinberg equation. There is no significant
association of the VDR gene FokI gene polymorphism
with prostate risk among prostate patients or healthy
controls participants. The frequency of FF genotype was
(30.7%) for prostate cancer patients compared with (28%)
for healthy control. Ff genotype frequency in prostate
cancer patients group was (61.3%) compared with (66%)
for healthy control. ff genotype frequency was (8.1%)
in prostate patients group compared to (6%) within the
healthy control group (Table 1).
Our results (table 2) showed that the mean serum level
of 25(OH)D for prostate patients (7.7±0.44 ng/ml) was
signicantly lower than the level in the control group (21.8
Table 1. Association of VDR Genotypic Frequencies
among Prostate Cancer and Control Participants in
Regard with Hardy-weinberg Equilibrium
Genotype Case n(%) Control n(%) P value
FF 38 (30.7) 28 (28) 0.719
Ff 76 (61.3) 66 (66)
Ff 10 (8.1) 6 (6)
Allele
F 152 (61.3) 122 (61) 0.95
F 96 (38.7 ) 78 (39)
Table 2. Serum 25(OH)D Mean Levels among Prostate
Cancer Patients and Control
N Mean±SE*(ng/ml) p value
Prostate cancer patients 124 7.7±0.44 0.001**
Control 100 21.8±0.56
*SE: Standard error of the mean. **p-value<0.05 is considered signicant

Asian Pacic Journal of Cancer Prevention, Vol 16, 2015 2229
DOI:http://dx.doi.org/10.7314/APJCP.2015.16.6.2227
The Fok1 Vitamin D Receptor Gene Polymorphism and 25(OH)D Levels and Prostate Cancer among Jordanian Men
ng/ml±0.56) (p-value=0.001).
The results of this study shows that there statistical
signicant difference in the mean 25(OH)D levels among
FF, Ff and ff genotypes within both prostate cancer patients
(p=0.036) and control (p=0.002)
Discussion
Vitamin D insufciency affects almost 50% of the
population worldwide. An estimated 1 billion people
worldwide, across all ethnicities and age groups, have a
vitamin D deciency (Nair and Maseeh, 2012). Prostate
cancer is one of the most common cancers among men,
it is the second leading cause of cancer deaths worldwide
(Siegel et al., 2013). Although it is less common in
developing countries, its incidence and mortality rate is
raised (Jemal et al., 2006). In Jordan and according to
ministry of health at the Hashemite Kingdom ((www.moh.
gov.jo)there were179 prostate cancer cases accounting
3.7% of all Jordanian cancer cases. Prostate cancer ranked
the sixth among Jordanian male cancers which accounted
(7.9%) of male cancers. Its etiology is unclear; however
it may be related to ethnicity, environmental, genetics,
hormonal and dietary factors (Tzonou et al., 1999;
Lichtenstein et al., 2000)
The reason why VDR gene polymorphism has attracted
attention because of the overall of anticancer effect of
vitamin D itself. A number of studies have examined the
role of VDR variants in prostate cancer with equivocal
results ranging from statistically signicant association
(Oakley-Girvanet al., 2004; Jemal et al., 2006), weak
association (Hayes et al., 2005) to no association (Guo et
al., 2013) between common VDR variants and prostate
cancer. Our nding showed no signicant association of
VDR Fok1 gene polymorphism with prostate cancer risk.
This is consistent with many previous studies (Yin et al.,
2009; Zhang and Shan, 2013; Yousaf et al., 2014) among
different ethnic groups.
Eighty three percent of the control participants in
this study are decient/insufcient for vitamin 25(OH)
D level. This high percentage is similar to the percentage
observed by Atoum and Tchoporyan (2014) among
Jordanians. Although Jordanian climate may offers
sufcient sunlight, the observed considerable deciency
and insufciency might be attributed to other factors
such as high pigmentation of Middle Eastern population,
working indoors most of the daytime and dietary style
(Nair and Maseeh, 2012).This study also shows that 17%
of control have optimal serum 25(OH)D level (more than
20 ng/ml), while only 3% of prostate cancer patients are
optimal. This study also shows that patients decient in
vitamin D (less than 10.0 ng/ml) had 35 fold increased
prostate cancer risk compared to control. While increasing
circulatory 25(OH)D level by adequate exposure to
sunlight or oral supplementation promote the prostate
cells to convert 25(OH)D to 1alpha 25(OH)D2 which
has an antiproliferative effect in prostate cells (Donkena
and Young, 2011). This nding shows that deciency in
25(OH)D might participate in prostate cancer development
and progression, and vitamin D level could be added as
an additional factor to consider before ordering a biopsy
for prostate cancer patients.
Our results showed signicant difference in the mean
of 25(OH)D level among various VDR Fok1 genotype (FF,
Ff, ff) within the prostate and control groups. Consitant
with our results, a prospective study observed that the
Fok1 gene polymorphism interacted with 25(OH)D and
modied prostate cancer risk in the presence of low
25(OH)D status (Li et al., 2007). On the other hand, Xu
et al (2003) showed that presence of an F allele increased
the risk of being diagnosed with more aggressive cancer
because higher percentage of Gleason grade 4/5 is
associated with worse prognosis. Huang et al (2006)
suggested that the VDR FokI FF genotype increased the
Figure 1. 2% Agarose Gel Electrophoresis for the
Genotypes After FokI Enzyme Digestion of the PCR
Product. Lane 1: 50bp DNA ladder. Lanes 2, 7, 8, 9, and 10:
Ff genotypes. Lane 6, 11, 12: FF genotype. Lanes 3, 4 and 5:
ff genotypes
Table 3. Association between 25(OH)D Level and Prostate Cancer Risk
(OH)D Status Prostate Cancer Patients N=124 Controls n=100 OR 95% CI
25(OH)D less than 10.0 ng/ml 86 (69.35%) 6 (6.00%) 35.45 (14.28-88.03)
10.0 ≤ 25(OH)D ≥20 ng/ml 34 (27.42%) 77 (77.00%) 0.11 (0.06-0.21)
25(OH)D more than 20 ng/ml 4 (3.23%) 17 (17.00%) 0.2 (0.05-0.50)
*Decient: less than 20ng/ml; Insufcient: between 10 and 20ng/ml; Optimal: more than 20ng/ml
Table 4. Serum 25(OH)D Mean Levels (ng/ml) for Each FokI Genotypes
Prostate Patients (n=124) Control (n=100)
VDR FokI N Mean ± Std (ng/ml) p-value VDR FokI N Mean ± Std (ng/ml) p-value
Genotype Genotype
FF 38 6.2±4.3 0.036 FF 28 19.0±5.5 0.002
Ff 76 8.2±4.2 Ff 66 22.5±5.1
ff 10 9.9±9.2 ff 6 26.3±6.5

Manar Fayiz Atoum et al
Asian Pacic Journal of Cancer Prevention, Vol 16, 2015
2230
risk of early-onset prostate cancer, especially its more
aggressive forms (Huang et al., 2006). Our data showed
that FF genotype associate with the lowest 25(OH)D
among both prostate cancer patients and control (6.2 and
19), respectively. The frequencies of the different Fok1
genotypes vary widely across different population and
ethnic groups most likely due to different population`s
diverse genetic behavior and exposure to mutagens leading
to mutations that can amplify infrequency in a population.
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