Vitamin D receptor gene polymorphisms and breast cancer risk.

PURPOSE: The steroid hormone 1,25-dihydroxyvitamin D3 is thought to protect against breast cancer. The actions of 1,25-dihydroxyvitamin D3 are mediated via the vitamin D receptor (VDR), and a number of polymorphisms in the VDR gene have been identified. These result in distinct genotypes, some of which may alter susceptibility to breast cancer. We have investigated whether specific VDR gene polymorphisms are associated with breast cancer risk in a United Kingdom Caucasian population. EXPERIMENTAL DESIGN: In a retrospective case-control study, female breast cancer patients (n = 398) and control women (n = 427) were recruited, and three VDR polymorphisms were determined. RESULTS: The 3' VDR polymorphisms BsmI and variable-length poly(adenylate) sequence were both significantly associated with breast cancer risk; odds ratios (adjusted for age menopausal status and hormone replacement therapy usage) for bb genotype versus BB genotype = 1.92 (95% confidence interval, 1.20-3.10; P < 0.01) and for LL versus SS = 1.94 (95% confidence interval, 1.20-3.14; P < 0.01). A 5' VDR gene variant, FokI, was not associated with breast cancer risk when analyzed in isolation (P > 0.05). However, FokI did modulate the increased risk associated with the bb/LL genotype such that possession of one or more F alleles together with the bb/LL genotype augmented breast cancer risk. Furthermore, the highest proportion of bb and FFLL/FfLL genotypes occurred in women with metastatic breast cancer. CONCLUSIONS: VDR polymorphisms are associated with breast cancer risk and may be associated with disease progression. Additional investigations into how different genotypes may affect the functional mechanisms of the VDR will provide a better strategy for identifying women at risk of breast cancer and for developing improved treatments.     

Association of A vitamin D receptor polymorphism with sporadic breast cancer development

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.     

Haplotype analysis of common vitamin D receptor variants and colon and rectal cancers.

Inherited variants of the vitamin D receptor (VDR) gene may influence cancer risk by altering the effect of vitamin D on cell growth and homeostasis. Studies have examined genotypes for common VDR polymorphisms, including a single nucleotide polymorphism (SNP) detected by Bsm1, a polyadenosine [poly(A)] repeat polymorphism, and a SNP detected by Fok1, as candidates for susceptibility to cancer, but most have not evaluated haplotypes for these markers. We investigated haplotypes for these polymorphisms in case-control studies of colon cancer (1,811 cases and 1,451 controls) and rectal cancer (905 cases and 679 controls). We used the expectation-maximization algorithm to estimate haplotypes for White, Hispanic, African-American, and Asian subjects, tested for differences in VDR haplotype distribution, and calculated odds ratios (OR) for association between haplotype and cancer. The distribution of haplotypes differed by race or ethnic group, but four common haplotypes accounted for the majority of alleles in all groups. VDR haplotype distributions differed between colon cancer cases and controls (P = 0.0004). The common haplotype bLF, containing Bsm1 b (Bsm1 restriction site present), poly(A) long (18-22 repeats), and Fok1 F (restriction site absent) was associated with increased risk of colon cancer, OR 1.15 (95% confidence interval, 1.03-1.28), as was the rare haplotype BLF, containing Bsm1 B (restriction site absent), poly(A) long, and Fok1 F (OR, 2.40; 95% confidence interval, 1.43-4.02). No case-control differences were detected for rectal cancer. In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables.     

Polymorphisms in the MTHFR and VDR genes and skin cancer risk

Folate and vitamin D have been shown to be influenced by ultraviolet (UV) radiation. UVA radiation can break down plasma folate, whereas vitamin D can be synthesized in UVB-exposed skin. Folate metabolism is involved in DNA synthesis and repair, and vitamin D processes anti-proliferative effects. The functions of both nutrients are implicated in skin carcinogenesis. We evaluated genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) and the vitamin D receptor (VDR) gene (Fok1, Bsm1 and Cdx2) with skin cancer risk in a nested case-control study within the Nurses' Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC) and 873 controls]. No significant associations were observed for the two MTHFR polymorphisms on skin cancer risk. We observed an interaction between the C677T polymorphism and total folate intake on SCC risk (P, interaction=0.04); the highest risk was observed among women with TT genotype and low folate intake (OR=2.14; 95% CI=1.01-4.50). The VDR Bsm1 BB genotype was significantly associated with an increased SCC risk (OR=1.51; 95% CI=1.00-2.28). An interaction between the Bsm1 polymorphism and total vitamin D intake on SCC was observed, with the highest risk seen in women with the BB genotype and high vitamin D intake (OR=2.38; 95% CI=1.22-4.62) (P, interaction=0.08). This study suggests a possible role of the polymorphisms in MTHFR and VDR interacting with dietary intakes of folate and vitamin D in skin cancer development, especially for SCC. Due to a large number of comparisons and tests, the possible associations should be interpreted with caution and confirmed by other studies.     

Dietary calcium, vitamin D, VDR genotypes and colorectal cancer

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when <60 years of age (OR = 0.62, 95% CI = 0.42-0.93). Examination of calcium in conjunction with VDR genotype showed that a significant 40% reduction in risk of rectal cancer was observed for the SS or BB VDR genotypes when calcium intake was low (p interaction = 0.01 for calcium interaction). For colon cancer, high levels of dietary intake of calcium, vitamin D, and low-fat dairy products reduced risk of cancer for the SS or BB VDR genotypes, although the p for interaction was not statistically significant. These data support previous observations that high levels of calcium and vitamin D reduce risk of rectal cancer and provide support for a weak protective effect for the SS and BB VDR genotypes. The risk associated with VDR genotype seems to depend upon the level of dietary calcium and vitamin D and tumor site.     

Vitamin D Receptor Poly(A) Microsatellite Polymorphism and 25-Hydroxyvitamin D Serum Levels: Association with Susceptibility to Breast Cancer

Purpose

According to previous studies, vitamin D exhibits protective effects against breast cancer via the vitamin D receptor (VDR). There is growing evidence that breast cancer incidence is associated with various polymorphisms of the VDR gene. This study investigates the association of VDR poly(A) microsatellite variants with 25-hydroxyvitamin D (25(OH)D) serum levels and breast cancer risk.

Methods

Polymorphism analysis was performed on a total of 261 blood samples, which were collected from 134 women with breast cancer and 127 controls. Single strand conformation polymorphism was assessed by polymerase chain reaction in combination with sequencing to detect poly(A) lengths for each sample. The vitamin D levels of samples were determined by electrochemiluminescence.

Results

The poly(A) variant L allele frequency was significantly higher in cancer patients than in controls (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.16-2.57; p=0.006). Thus, carriers of the L allele (LS and LL genotypes) have a higher risk for breast cancer (OR, 1.86; 95% CI, 1.13-3.05; p=0.013). A larger increase in the risk for breast cancer was found in individuals with the L carrier genotype and lowered 25(OH)D levels.

Conclusion

The results primarily suggest that VDR gene polymorphism in the poly(A) microsatellite is associated with 25(OH)D levels and that it can affect the breast cancer risk in the female population from northern Iran.     

Do VDR Gene Polymorphisms Contribute to Breast Cancer?

Breast cancer is the first or second leading cancer among females across the globe. A large number of studies have been conducted to assess any relationship between vitamin D receptor (VDR) gene polymorphisms and breast cancer development. Epidemiological studies have indicated that ethnic traits exhibited by a group of people with a common ancestry and culture, alter the link between VDR gene and breast cancer. It has been hypothesized that VDR polymorphisms have the capacity to impact both on incidence of breast cancer occurrence and to predict its outcome. A survey was here conducted to assess and compare the impact of vitamin D receptor gene polymorphisms Fok1, Bsm1, Taq1, Apa1 and poly (A) on development of breast cancer. Information was obtained from electronic databases including PubMed and Google Scholar for articles published during the period from 1996 to 2015. This search was achieved by using the terms “genetics”, “breast cancer”, “VDR gene”, “polymorphisms”. However, due to inconsistent results, no conclusive statements could be presented about the significance of the VDR genotype as far as the development of breast carcinoma is concerned’     

Vitamin D receptor gene ApaI polymorphism and breast cancer susceptibility: a meta-analysis

Vitamin D receptor (VDR) principally mediates the anticancer activities of vitamin D. Many studies investigated the association between VDR gene ApaI polymorphism and breast cancer, but the results were inconclusive. We performed this meta-analysis to evaluate the association between VDR gene ApaI polymorphism and breast cancer. Twelve studies with a total of 8,254 subjects were identified from PubMed and Wanfang databases. The pooled odds ratio (OR) and confidence intervals (95 % CI) were used to assess the association. The meta-analysis indicated that VDR gene ApaI polymorphism was not associated with risk of breast cancer (a vs. A: OR?=?0.97, 95 % CI 0.91–1.04, P?=?0.378; aa vs. AA: OR?=?0.97, 95 % CI 0.85–1.10, P?=?0.618; aa vs. AA + Aa: OR?=?1.00, 95 % CI 0.89–1.12, P?=?0.972; aa + Aa vs. AA: OR?=?0.95, 95 % CI 0.82–1.11, P?=?0.550). Subgroup analysis by ethnicity further showed that VDR gene ApaI polymorphism was not associated with risk of breast cancer in both Asians and Caucasians. These data from the meta-analysis indicate that VDR gene ApaI polymorphism is not associated with breast cancer susceptibility.     

Association of breast cancer progression with a vitamin D receptor gene polymorphism. South-East Sweden Breast Cancer Group.

The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1alpha,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age, <37 years) and a control population (n = 130), revealed no overall association to risk for breast cancer. However, patients without TaqI site (TT genotype) showed a significantly increased risk for lymph node metastasis (relative risk, 1.8, 95% confidence interval, 1.3-2.6). Furthermore, a tendency toward an increased survival was found among estrogen receptor-positive, tamoxifen-treated patients who were homozygous for the TaqI site (P = 0.075). We conclude that polymorphism in the VDR gene may influence tumor progression and tamoxifen treatment response in early-onset breast carcinomas.     

Associations between androgen and Vitamin D receptor microsatellites and postmenopausal breast cancer.

We investigated the association between polymorphism in the androgen receptor (AR) and vitamin D receptor (VDR) genes and breast cancer risk in a large population-based case-control study of genetically homogenous Swedish women. We successfully determined both AR CAG(n) and VDR A(n) genotype in 1,502 women with invasive breast cancer and in 1,510 control women. We did not find any associations between AR or VDR microsatellite lengths and breast cancer when we used a priori determined cutoffs (/=22 repeats for AR and /=19 for VDR) to define long and short alleles. There was statistically significant interaction between VDR genotype and parity, such that women with two short alleles had a halved risk for breast cancer, irrespective of parity, compared with nulliparous women with two long alleles. Homozygosity for the long VDR allele was associated with a more advanced clinical stage at diagnosis. In exploratory analyses, we determined cutoffs based on visual inspection of distributions of allele lengths among cases and controls and found that women carrying two alleles with <20 AR CAG(n) repeats had an increased risk for breast cancer, odds ratio of 1.67 (95% confidence interval, 1.17-2.38), compared with those with two alleles with >/=20 repeats. Women carrying two VDR alleles with <21 A(n) were also at an increased risk, odds ratio of 1.26 (95% confidence interval, 1.04-1.51). Our data do not support major roles for AR or VDR polymorphism as breast cancer risk factors. However, we did find an interaction between VDR genotype and parity that remains to be corroborated.     

Association between vitamin D receptor poly(A) polymorphism and breast cancer risk: a meta-analysis

Vitamin D receptor (VDR) poly(A) is a common genetic polymorphism in the VDR gene, and it has been implicated to be associated with breast cancer risk. However, previous studies on the association reported inconclusive results. We performed this meta-analysis to comprehensively assess the association. Eligible studies were searched in PubMed and EMBASE databases. Odds ratio (OR) and its 95 % confidence interval (95 % CI) were used for statistical analysis. A total 6,631 cases and 6,718 controls from 11 case–control studies were finally included into the meta-analysis. Meta-analysis of total eligible studies showed that VDR poly(A) polymorphism was not associated with the risk of breast cancer (S versus L: OR?=?0.99, 95 % CI of 0.90–1.09, P?=?0.84; SS versus LL: OR?=?0.96, 95 % CI of 0.79–1.18, P?=?0.70; SS/LS versus LL: OR?=?0.96, 95 % CI of 0.83–1.12, P?=?0.63; SS versus LL/LS: OR?=?1.00, 95 % CI of 0.91–1.10, P?=?0.98). Meta-analysis of studies with high quality also showed that there was no association between VDR poly(A) polymorphism and breast cancer risk. In addition, in the subgroup analysis by ethnicity, no significant association was found among Caucasians. Therefore, the meta-analysis suggests that VDR poly(A) polymorphism is not associated with the risk of breast cancer. Large well-designed studies are necessary to clarify the possible association in Asians.     

Circulating vitamin D metabolites, polymorphism in vitamin D receptor, and colorectal adenoma risk.

OBJECTIVE: Vitamin D is a potential agent for the prevention of colorectal cancer possibly through mechanisms mediated by the vitamin D receptor (VDR). We investigated the association of circulating vitamin D metabolites and a genetic variant of the VDR gene with advanced colorectal adenoma, a precursor lesion of colorectal cancer. METHODS: Cases with advanced adenoma of the distal large bowel and gender- and ethnicity-matched controls with a negative sigmoidoscopy were randomly selected from participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Genotype analysis of the VDR TaqI polymorphism was completed on 763 cases and 774 controls. Serum levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] were measured in a subset of 394 cases and 397 controls. RESULTS: Serum levels of 25(OH)D were inversely associated with advanced adenoma risk in women but not in men. Comparing those in the highest quintile with those in the lowest quintile, the risk for advanced adenoma decreased by 73% in women [odds ratio (OR) = 0.27, 95% confidence interval (95% CI) = 0.11-0.69; P for trend = 0.0002], while the risk did not decrease in men (OR = 1.10, 95% CI = 0.60-2.05; P for trend = 0.85). In women, 25(OH)D levels were significantly higher in current users of hormone replacement therapy (HRT) than in former or never HRT users. Neither serum 1,25(OH)(2)D nor VDR TaqI genotype was associated with advanced adenoma risk. CONCLUSION: Higher serum 25(OH)D levels were associated with decreased adenoma risk. Serum 1,25(OH)(2)D and VDR TaqI genotype were not associated with adenoma risk.     

Genetic determinants of bone mass do not relate with breast cancer risk in US white and African-American women

Introduction The association between high bone mass and increased breast cancer risk has been established. Identification of polymorphisms and the resultant variant receptors suggests the possibility of differential effects on hormone responsive genes when complexed with the hormones. Both estrogen receptor-α (ER) and vitamin D receptor (VDR) polymorphisms have been associated with bone density. Thus, we examined these polymorphisms for association with increased breast cancer risk among US African-American and white women.Methods A case–control study was conducted to measure ER and VDR polymorphisms and radial bone mineral density (BMD) in African-American and white women, and to examine the association between polymorphisms, bone density and breast cancer risk. Genotypes and bone density were obtained from 412 women (220 cases and 192 controls, with equal distribution between the two ethnic groups).Results We found no evidence for an association between either the ER or VDR genotypes and breast cancer risk. Also, there was no difference in the risk of breast cancer by genotypes after adjusting for ethnicity. The addition of age, sex and ethnicity-specific BMD (Z-scores) did not significantly change the odds ratio for breast cancer.Conclusions Our data suggest that the polymorphisms investigated had no effect on risk of breast cancer in this population. Thus, we found no evidence to support our hypothesis that breast cancer cases and controls would have a different distribution of ER and VDR genotypes. Furthermore, the polymorphisms were not associated with differences in bone mass and its relationship with breast cancer risk.     

Vitamin D receptor genotype and breast cancer in Latinas (United States)

Objective: Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk.Methods: Polymorphisms in the 5 and 3 ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls.Results: Both the BsmI and poly-A polymorphisms in the 3 end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0–2.3) and 3.2 (1.5–6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1–2.5) and 2.2 (1.0–4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk.Conclusion: These results suggest that polymorphic variation in or near the 3 end of the VDR gene influences breast cancer risk in Latina women.     

CDX2 VDR polymorphism and colorectal cancer.

Studies suggest that polymorphisms of the vitamin D receptor (VDR) gene may influence colorectal cancer risk. In this study, we examine the association of the CDX2 VDR polymorphism (rs11568820) located in the 5'-untranslated region of the gene, and VDR haplotypes, including this polymorphism, with colon and rectal cancer using data from two large case-control studies of colon (N = 1,574 cases and 1,970 controls) and rectal (n = 791 cases and 999 controls) cancer. The frequency of the A allele of the CDX2 polymorphism was 19% among non-Hispanic white, 21% among Hispanic, 76% among African American, and 47% among Asian controls. The CDX2 polymorphism was not independently associated with either colon or rectal cancer, nor did it modify associations of dietary calcium, vitamin D, or fat with colon or rectal cancer. However, the bLFA haplotype which occurred in 6.5% of non-Hispanic white participants and 41.2% of African American participants was associated with an increased risk of colon cancer, and an odds ratio of 2.4 [95% confidence intervals (CI), 2.45 (1.38-4.38)]. The BSfG haplotype was associated with a 1.61 (95% CI, 1.05-2.49) increased risk of rectal but not colon cancer, whereas the BSFA haplotype was associated with a significantly reduced risk of rectal (odds ratio, 0.71; 95% CI, 0.52-0.97) but not colon cancer. These data suggest that haplotype analysis that encompasses different domains of the VDR gene might further our understanding of associations between the VDR gene and colon and rectal cancer.     

The VDR gene FokI polymorphism and ovarian cancer risk

The polymorphism of vitamin D receptor (VDR) gene is demonstrated to affect the activity of its encoding protein and the subsequent downstream effects mediated by vitamin D. Mutations in VDR gene FokI have been suggested in the development of various cancers. Whether the polymorphism of the VDR gene FokI confers risk to ovarian cancer still remains controversial across the published studies in different ethnicity. The aim of this meta-analysis was to determine the role of VDR gene FokI variant in the susceptibility to ovarian cancer. Six publications with 14 individual case–control studies involving a total of 10,964 subjects were finally included into our study after a comprehensive literature search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association between the VDR gene FokI polymorphism and ovarian cancer risk was estimated under the allelic (T vs. C), homozygous (TT vs. CC), additive (CT vs. CC), recessive (TT vs. CC + CT), and dominant (CT + TT vs. CC) gene models. The overall odds ratios (ORs) for the contrast models of T vs. C, TT vs. CC, CT vs. CC, and CT + TT vs. CC indicated that the VDR gene FokI variant was related to an increased risk of ovarian cancer (OR_{T vs. C}?=?1.09, 95 % confidence interval (CI) 1.03–1.15, P _OR?=?0.004; OR_{TT vs. CC}?=?1.17, 95 % CI 1.04–1.32, P _OR?=?0.011; OR_{CT vs. CC}?=?1.10, 95 % CI 1.01–1.20, P _OR?=?0.027; OR_{CT + TT vs. CC}?=?1.12, 95 % CI 1.03–1.21, P _OR?=?0.007). The stratified analysis among the Caucasians also identified a significant association between the VDR gene FokI polymorphism and the susceptibility to ovarian cancer. The present meta-analysis with large available published data has revealed that the VDR gene FokI polymorphism confers susceptibility to ovarian cancer, particularly among the Caucasian population.     

Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population

Low levels of 25-hydroxy vitamin D (25(OH)D) and polymorphisms in the vitamin D receptor gene (VDR) have been found separately to increase risk of breast cancer. The aim of this study was to determine whether low 25(OH)D levels, alone and in combination with BsmI VDR genotype, increased breast cancer risk in a United Kingdom (UK) Caucasian population. Breast cancer patients (n=179) and control women (n=179) were recruited and 25(OH)D levels measured by enzyme-linked immunosorbent assay (ELISA). VDR genotype was determined by polymerase chain reaction (PCR) and restriction enzyme digest. Analysis showed that subjects with 25(OH)D levels <50 nM and the bb BsmI VDR genotype are 6.82 times more likely to have breast cancer than subjects with levels of 25(OH)D>50 nM and either the BB or Bb genotype (95% confidence interval (CI) 2.31-14.7, P<0.001). This study indicates that low levels of circulating 25(OH)D, both alone and in combination with BsmI VDR genotype, may increase risk of breast cancer in a UK Caucasian population.     

Association of ApaI and TaqI polymorphisms in VDR Gene with Breast Cancer

Background: Vitamin D inhibits cell proliferation via the vitamin D receptor (VDR), which may affect breast cancer risk. This study aimed to investigate the association of ApaI and TaqI polymorphisms of the VDR gene with breast cancer risk which followed by stratified analysis. Materials and methods: A case-control study was conducted on 150 breast cancer patients and 150 healthy controls. VDR ApaI and TaqI genotyping were performed by PCR-RFLP. Some demographic and pathologic features of patients were extracted from their archived files and then were analyzed by genotypes distributions. Results: For ApaI polymorphism, our data showed a significant difference between the patient and healthy groups for mutant allele carriers compared with those with AA genotype. Besides, statistical analysis showed that there was a significant association between the C allele and the increased risk of breast cancer. For TaqI polymorphism, statistical analysis revealed that there was a significant association between CC genotype and increased risk of breast cancer. Also, there was a significant association between the C allele and the increased risk of breast cancer. In a preliminary study, stratified analysis based on the size of tumor and lymph node metastasis revealed no significant association between two ApaI and TaqI variations and these parameters. Conclusions: Based on our results, the VDR ApaI and TaqI variations could be considered as genetic risk factors for breast cancer. However, further studies with a larger sample size are required to obtain more accurate outcomes, especially in stratified analysis.