Association between VDR Gene Polymorphisms (rs 1544410, rs 7975232, rs 2228570, rs 731236, rs 11568820) and Susceptibility to Breast Cancer in a Sample of Southeastern Iranian Population

Abstract

Background: Vitamin D receptor (VDR) is a key nuclear receptor that is associated with the risk and progression of breast cancer (BC). Objectives: The present study investigated the Fok1, Bsm1, Taq1 and Cdx2 polymorphisms in the VDR gene and susceptibility to BC in a sample of Southeastern Iranian population. Methods: This case-control study was conducted on 180 women with BC and 178 age-matched healthy women. RFLP-PCR method was used for analysis of Bsm1 (rs 1544410), Apa1 (rs 7975232), Fok1 (rs 2228570) and Taq1 (rs 731236) and also TETRA-ARMS method for Cdx2 (rs 11568820). Results: No significant correlation was found between polymorphisms of Taq1, Fok1 and Apa1 with BC, but was for Bsm1 (odds ratio (OR) = 3.452, 95% CI 1.769-6.738; P < 0.001). Also, there was a significant correlation between the case and control groups for Cdx2 (OR = 3.720, 95% CI 2.224-6.225; P < 0.001) and allele A in Cdx2 had just significant correlation with BC. Conclusions: The present study findings showed that there were significant correlations between Bsm1 and Cdx2 polymorphisms with BC in women of Sistan and Baluchestan Province (southeastern Iran). Also, signals of Rs1544410-Bsm1 and Rs11568820-Cdx2 positions were difference with routes of estrogen and progesterone per person and they probably act independently.

Full text

Int J Cancer Manag. In Press(In Press):e8807.
Published online 2017 March 26.
doi: 10.5812/ijcm.8807.
Research Article
Association between VDR Gene Polymorphisms (rs 1544410,rs 7975232,
rs 2228570,rs 731236,rs 11568820) and Susceptibility to Breast Cancer in
a Sample of Southeastern Iranian Population
Seyed Mehdi Hashemi,1Narges Arbabi,2,* Mohammad Hashemi,3Mohammad Ali Mashhadi,1
Abolghasem Allahyari,4and Masoud Sadeghi5
1Department of Internal Medicine, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
2Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
3Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
4Department of Hematology and Medical Oncology, Mashhad University of Medical Sciences, Mashhad, Iran
5Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
*Corresponding author: Narges Arbabi, Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran. Tel: +98-5433295763,
Fax: +98-533294390, E-mail: narges.arbabi@gmail.com
Received 2016 September 07; Revised 2016 December 04; Accepted 2017 March 01.
Abstract
Background: Vitamin D receptor (VDR) is a key nuclear receptor that is associated with the risk and progression of breast cancer
(BC).
Objectives: The present study investigated the Fok1,Bsm1,Taq1 and Cdx2 polymorphisms in the VDR gene and susceptibility to BC in
a sample of Southeastern Iranian population.
Methods: This case-control study was conducted on 180 women with BC and 178 age-matched healthy women. RFLP-PCR method
was used for analysis of Bsm1 (rs 1544410), Apa1 (rs 7975232), Fok1 (rs 2228570) and Taq1 (rs 731236) and also TETRA-ARMS method for Cdx2
(rs 11568820).
Results: No significant correlation was found between polymorphisms of Taq1,Fok1 and Apa1 with BC, but was for Bsm1 (odds ratio
(OR) = 3.452, 95% CI 1.769 - 6.738; P < 0.001). Also, there was a significant correlation between the case and control groups for Cdx2
(OR = 3.720, 95% CI 2.224 - 6.225; P < 0.001) and allele A in Cdx2 had just significant correlation with BC.
Conclusions: The present study findings showed that there were significant correlations between Bsm1 and Cdx2 polymorphisms
with BC in women of Sistan and Baluchestan Province (southeastern Iran). Also, signals of Rs1544410-Bsm1 and Rs11568820-Cdx2 posi-
tions were difference with routes of estrogen and progesterone per person and they probably act independently.
Keywords: Breast Cancer, Polymorphism, VDR, Southeastern Iran
1. Background
Breast cancer (BC) is the most frequent malignancy
among women (1) that is the second leading cause in low
and middle income countries (2). Inherited genetic risk
factors contribute toward BC onset and the discovery of
new BC susceptibility genes is critical for improved risk
assessment and to provide insight toward disease mecha-
nisms for the development of more effective therapies (3).
As in Iran, since the onset of the disease is at low age, in
spite of the relatively high survival rate as compared to
other cancers, prevention and screening programs at early
age for early stage diagnosis seem necessary (4). A com-
bination of family- and population-based approaches in-
dicated that genes involved in DNA repair are associated
with moderate BC risk (5). The genetic factors known to
be involved in BC risk comprise about 30 genes (6), the
risk of some of them has been reported in Iranian people
with BC (7-9). Vitamin D (1, 25-dihydroxyVitamin D3) has
been shown experimentally to have anti-carcinogenic ef-
fects and is thought to inhibit BC (10). Vitamin D is hypoth-
esized to lower the risk of BC by inhibiting cell prolifera-
tion via the nuclear vitamin D receptor (VDR) (11). There-
fore, the actions of Vitamin D are mediated via the VDR,
and the polymorphisms at 3’UTR region (four important
single nucleotide polymorphisms (SNPs) in exon 2 includ-
ing VDR-Fok1 (rs 2228570), VDR-Bsm1 (rs 1544410), VDR-Taq1 (rs
731236) and VDR-Apa1 (rs 7975232) (12) of this gene are asso-
ciated with the risk and progression of breast carcinoma
(10). Also, the VDR is a key nuclear receptor that binds nu-
tritionally derived ligands and exerts bio-effects that con-
tribute to bone mineral homeostasis, detoxification of ex-
ogenous and endogenous compounds, cancer prevention,
and mammalian hair cycling (13). VDR-Cdx2 is another poly-
morphism of the VDR. There are limited studies on the re-
Copyright © 2017, International Journal of Cancer Management. This is an open-access article distributed under the terms of the Creative Commons
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UnCorrected Proof

Hashemi SM et al.
lationship between it and BC’s unfavorable biopatholog-
ical characteristics (14). Therefore, these polymorphisms
change the codons that alter the function of VDR protein.
2. Objectives
In the present study, we investigated the Fok1,Bsm1,Taq1
and Cdx2 polymorphisms in the VDR gene and susceptibil-
ity to BC in a sample of Southeastern Iranian population.
3. Methods
3.1. Patients
This study was approved by the ethical committee
of Zahedan University of Medical Sciences (Grant num-
ber: 6796 and Ethical Code: IR.ZAUMS.REC1393.6796). In
a cross-control study, 180 BC and 178 control women (age-
matched) who referred to Ali-ibn Abi Talib hospital and pri-
vate centers, Zahedan, Iran were chosen. The controls did
not have any relationship with patients and had no history
of cancer.
3.2. Immunohistochemical (IHC) Analysis
Estrogen receptor (ER) and progesterone receptor (PR)
positivity, defined as ≥10% positive tumor cells with nu-
clear staining (15). Also, for HER2 2+ based on IHC, chro-
mogenic in situ hybridization (CISH) identified HER2 gene
amplification for determination of HER2 status.
3.3. VDR Genotype Analysis
Blood samples of the controls and patients were gath-
ered in tubes with EDTA, and DNA was extracted with salt-
ing out method (16). RFLP-PCR method was used for anal-
ysis of rs 1544410,rs 7975232,rs 2228570, and rs 731236 while
TETRA-ARMS method was used for rs11568820. Primer se-
quence and reaction conditions have been shown in Ta-
ble 1. The amplified PCR products were digested with
Taq1,Apa1,Bsm1 and Fok1 restriction endonuclease enzymes
(Thermo Scientific Company, USA) overnight (16 hours) at
temperatures 65°C, 37°C, 37°C and 55°C respectively. The
PCR conditions for VDR polymorphisms (Taq1,Fok1,Apa1
and Bsm1) were: The initial denaturation in 95°c for 5 min-
utes and after that, thirty cycles in 95°C for 30 seconds, 68°C
for 30 seconds, 72°C for 30 seconds and at last, 72°C for 5
minutes. Then, products of PCR with 2% agarose gel and 0.5
µg/mL Ethidium bromide were loaded and observed under
UV light. At last, each site was digested with specific en-
zyme. The PCR conditions for Cdx2 was: The initial denat-
uration in 95°C for 5 minutes and after that, thirty cycles
in 95°C for 30 seconds, 58°C for 30 seconds, 72°C for 30 sec-
onds and at last, 72°C for 5 minutes.
3.4. Statistical Analysis
The analysis was done using SPSS 22 software (IBM, SPSS
Inc., Chicago, IL, USA). The logistic regression analyses were
assessed by computing the odds ratio (OR) and 95% confi-
dence intervals (CI) for association between genotypes and
BC. Also, a p-value < 0.05 was considered to be statistically
significant.
4. Results
The mean age of the case and control groups were 47.93
years and 48.28 years, respectively. Table 2 shows a number
of variables in the patients. The prevalence of genotypes in
two groups has been shown in Table 3. There was no sig-
nificant correlation between polymorphisms of Taq1,Fok1
and Apa1 with BC, but there was for Bsm1 (OR = 3.452, 95%
CI 1.769 - 6.738; P < 0.001). Also, there was a significant cor-
relation between the case and control groups for Cdx2 (OR
= 3.720, 95% CI 2.224 - 6.225; P < 0.001) and allele A in Cdx2
had just significant correlation with BC.
The correlation between five genotypes and three re-
ceptors in BC patients have been shown in Table 4. There
was just a significant correlation between Fok1 and HER2
status (P = 0.025).
5. Discussion
This study showed that there were significant correla-
tions between polymorphisms of VDR, such as Bsm1 and
Cdx2, and risk of BC in women of Sistan and Baluches-
tan province (southeastern Itan). These polymorphisms,
based on their position at the beginning of VDR gene, im-
pacted translation and ultimately levels of expression of
these protein. The OR for BC in association with Bsm1 and
Cdx2 was (OR = 0.4, 95% CI 0.222 - 0.721; P < 0.05) and
(OR = 0.29, 95% CI 0.148 - 0.565; P < 0.05), respectively.
Guy et al. (17) reported that VDR polymorphisms are as-
sociated with BC risk and may be associated with disease
progression in United Kingdom Caucasian population and
Chandler et al. (3) showed that they are associated with
BC in African-Americans, but not in Hispanic/Latinas and
that the Fok1FF genotype is linked with poor prognosis in
African-American women with BC. The results of one study
(18) suggested that Cdx2 polymorphism was a potential
biomarker for vitamin D treatment in BC, independent of
the VDR receptor expression, and another study reported
the Bsm1 associated with BC risk, with a trend for increas-
ing risk with increasing number of Bsm1 B alleles in Latina
women (19) and the b allele in Pakistani women (20). In
addition, Bsm1 genotype significantly modified the associ-
ation between dietary vitamin D and BC overall (21). The
2Int J Cancer Manag. In Press(In Press):e8807.
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Hashemi SM et al.
Table1. Primer Sequence and Reaction Conditions
SNP Primer sequence Restriction enzyme Product size (bp) Annealing
rs 1544410
Forward: 5-AACCAAGACTACAAGTACCGCGTCAGTGA-3 (30bp)
Bsm1
GG 650 + 175
68˚C
AG 825 + 650 + 175
Reverse: 5-AACCAGCGGAAGAGGTCAAGGG-3 (22bp) AA 825
rs 7975232
Forward: 5-GCAACTCCTCATGGCTGAGGTCTCA-3 (25bp)
Apa1
TT 745
68˚C
Reverse: 5-AGAGCATGGACAGGGAGCAAG-3 (21bp)
GT 745 + 528 + 217
GG 528 + 217
rs 2228570
Forward:5-ATGGAAACACCTTGCTTCTTCTCCCTC-3 (27bp)
Fok1
FF 272
68˚C
Ff 272 + 198 + 74
Reverse: 5-ATGCCAGCTGGCCCTGGCACTG-3 (22bp) Ff 198 + 74
rs 731236
Forward: 5-GCAACTCCTCATGGCTGAGGTCTCA-3 (25bp)
Taq1
CC 294 + 251 + 201
68˚C
TC 493 + 294 + 251 + 201
Reverse: 5-AGAGCATGGACAGGGAGCAAG-3 (21bp) TT 493 + 251
rs 11568820
F1: 5’-AGGATAGAGAAAATAATAGAAAACATT-‘3 (27bp)
Cdx2
GG 297 + 110
58˚C
R1: 5’-AACCCATAATAAGAAATAAGTTTTTAC-‘3 (27bp) AG297 + 235 + 110
F2: 5’-TCCTGAGTAAACTAGGTCACAA-‘3 (22bp)
AA 297 + 235
R2: 5’-ACGTTAAGTTCAGAAAGATTAATTC-‘3 (25bp)
Table2. Demographic Variables in Breast Cancer Patients (n = 180)a
Variable Patients group
Age
≥50 67 (39.4)
> 50 103 (60.6)
TNM Stage
I 25 (14)
II 75 (41.9)
III 50 (27.9)
IV 29 (16.2)
Grade
I 28 (19)
II 92 (62.6)
III 27 (18.4)
ER status
Positive 105 (61)
Negative 67 (39)
HER2 status
Positive 88 (49.4)
Negative 90 (50.6)
PR status
Positive 97 (56.7)
Negative 74 (43.3)
aValues are expressed as N. (%).
Pakistani authors (22) offered that the GG genotype of Cdx2-
VDR gene polymorphism may increase the risk of devel-
oping BC in young female patients in South Pakistan. The
authors of one research concluded that the common ge-
netic variants in vitamin D genes (Bsm1,Apo1,Fok1 and Taq1)
were not risk factors for BC in Chinese women (23). Also,
the current analysis suggested that they may not be asso-
ciated with BC risk in Caucasian women (24) and a meta-
analysis study confirmed this result in Caucasian popula-
tion (25). The results of Tang et al. (26) showed that there
were not significant associations between the Bsm1,Apa1
and Taq1 variants and risk of BC. Apa1 and Taq1and Fok1 were
tested for association with BC risk in 135 females with spo-
radic BC and 110 cancer-free female controls (27) where al-
lele frequencies of Apa1 polymorphism showed a signifi-
cant association, while the Taq1 showed a similar trend, but
the Fok1 polymorphism were not significantly different in
the study population. Chen et al. (28) observed a signifi-
cantly increased risk of BC among carriers of the ff geno-
type of Fok1 compared with those with FF, but did not ob-
serve an association between polymorphisms in BsmI and
BC risk for BB versus bb. Therefore, the results suggested
that the VDR may be a mediator of BC risk and could rep-
resent a target for cancer prevention efforts. Shahbazi et
al. (29) concluded that statistically significant association
between Fok1 genotypes and BC risk was not observed, but
there was an increased risk of BC associated with the BsmI
polymorphism (Bsm1 bb or even Bb genotype) in Tehran
(Central Iran).
In conclusion, the present study findings showed that
there were significant correlations between Bsm1 and Cdx2
polymorphisms, and BC in women of Sistan and Baluches-
Int J Cancer Manag. In Press(In Press):e8807. 3
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Hashemi SM et al.
Table3. The Exact Prevalence of Genotypes in Two Groups
Variabes Case GroupaControl GroupaOR P Value
Rs1544410-Bsm1
GG 14 (7.8) 35 (19.7) 1 < 0.001
AG 145 (80.6) 105 (59) 3.452 (1.769 - 6.738) < 0.001
AA 21 (11.6) 38 (21.3) 1.382 (0.610 - 3.129) 0.438
Allele
G 157(45.63) 175 (49.15) 1 -
A 187 (54.36) 181 (50.85) 1.15 (0.86 - 1.55) 0.364
Rs7975232-Apa1
TT 45 (25) 52 (29.2) 1 0.263
GT 124 (68.9) 121 (68) 0.393 (0.127 - 1.218) 0.106
GG 11 (6.1) 5 (2.8) 0,466 (0.157 - 1.380) 0.168
Allele
T 214 (59.45) 225 (63.21) 1 -
G 146 (40.55) 131 (36.79) 1.17 (0.87 - 1.58) 0.319
Rs2228570-Fok1
FF 98 (54.4) 88(49.4) 1 0.297
Ff 72 (40) 84 (47.2) 0.668 (0.233 - 1.914) 0.453
Ff 10 (5.6) 6 (3.4) 0.514 (0.178 - 1.484) 0.219
Allele
F 268 (74.45) 260 (73.04) 1 -
F 92 (25.55) 96 (26.96) 0.93 (0.67 - 1.29) 0.672
Rs731236-Taq1
TT 79 (43.9) 83 (46.6) 1 0.253
TC 90 (50) 77 (43.3) 1.558(0.692 - 3.504) 0.284
CC 11 (6.1) 18 (10.1) 1.913 (0.851 - 4.297) 0.116
Allele
T 248 (68.88) 243 (68.25) 1 -
C 112 (31.12) 113 (31.75) 0.97 (0.71 - 1.33) 0.872
Rs11568820-Cdx2
GG 26(14.4) 69 (38.8) 1 < 0.001
AG 150 (83.4) 107 (60.1) 3.720 (2.224 - 6.225) < 0.001
AA 4(2.2) 2 (1.1) 5.308 (0.917 - 30.736) 0.06
Allele
G 202 (56.12) 245 (68.82) 1 -
A 158 (43.88) 111 (31.18) 1.73 (1.27 - 2.34) < 0.001
aValues are expressed as N. (%).
tan province (southeastern Itan). Also, signals of Rs1544410-
Bsm1 and Rs11568820-Cdx2 positions were different with
routes of ER and PR per person and they probably act in-
dependently. Therefore, studies with more sample sizes
and in different ethnicities and long-term follow-up are re-
quired to confirm our finding.
4Int J Cancer Manag. In Press(In Press):e8807.
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Hashemi SM et al.
Table4. The Correlation Between Genotypes and Receptors in Breast Cancer Patients
Variables Bsm1 P Value
GG, N = 14 AG, N = 137 AA, N = 21
ER, Positive 8 ( 57.1) 87 ( 63.5) 10 ( 47.6) 0.362
PR, Positive 9 ( 64.3) 77 ( 56.6) 11 ( 52.4) 0.783
HER2, Positive 7 ( 50) 68 ( 47.6) 13 ( 61.9) 0.470
Cdx2
GG, N = 26 AG, N = 148 AA, N = 4
ER, Positive 13 ( 50) 73 ( 49.3) 2 ( 50) 0.998
PR, Positive 13( 54.2) 83 ( 58) 1 ( 25) 0.406
HER2, Positive 16 ( 64) 86 ( 60.1) 3 ( 75) 0.791
Fok1
FF, N = 93 Ff, N = 69 ff, N = 10
ER, Positive 55( 59.1) 43 ( 62.3) 7 ( 70) 0.796
PR, Positive 53 ( 57.6) 39 ( 56.5) 5 ( 50) 0.898
HER2, Positive 53 ( 54.6) 34 ( 47.9) 1 ( 10) 0.025
Taq1
TT, N = 78 TC, N = 89 CC,N = 11
ER, Positive 43 ( 55.1) 55 ( 66.3) 7 ( 63.6) 0.345
PR, Positive 45( 58.4) 46 ( 55.4) 6 ( 54.5) 0.918
HER2, Positive 34 ( 43.6) 50 ( 56.2) 4 ( 36.4) 0.179
Apa1
TT, N = 44 GT, N = 117 GG, N = 11
ER, Positive 28 ( 63.6) 71 ( 60.7) 6 ( 54.5) 0.850
PR, Positive 21 ( 47.7) 70 ( 60.3) 6 ( 54.5) 0.351
HER2, Positive 23 ( 51.1) 53 ( 51.6) 2 ( 18.2) 0.101
Acknowledgments
There is no acknowledgements.
Footnotes
Authors’ Contribution: Seyed Mehdi Hashemi and Mo-
hammad Hashemi were supervisor and designed the
study. Narges Arbabi was the corresponding author; wrote
the article, prepared the proposal and extracted the gene
polymorphisms of blood samples. Mohammad Ali Mash-
hadi analyzed the data, checked the gene polymorphisms
and the proposal. Abolghasem Allahyari and Masoud
Sadeghi revised the article.
Conflict of Interests: There is no conflict of interest.
Financial Disclosure: There is no financial disclosure.
Funding/Support: Zahedan University of Medical Sci-
ences, Zahedan, Iran.
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