Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis.

Several polymorphisms in the vitamin D receptor (VDR) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 14 studies (17 comparisons) with TaqI genotyping (1870 prostate cancer cases; 2843 controls), 6 studies (8 comparisons) with poly(A) repeat genotyping (540 cases; 870 controls), 5 studies with BsmI genotyping (987 cases; 1504 controls), and 3 studies with FokI genotyping (514 cases; 545 controls). The random-effects odds ratio (OR) for the t versus T allele was 0.95 [95% confidence interval (CI), 0.86-1.05]. There was no suggestion of an overall effect either in recessive or dominant modeling, and the comparison of t/t versus T/T also showed no differential prostate cancer susceptibility (OR, 0.88; 95% CI, 0.70-1.10). No effect of t was seen in subjects of European descent (nine comparisons; OR, 0.97; 95% CI, 0.87-1.08), Asian descent (five comparisons; OR, 0.88; 95% CI, 0.66-1.17), or African descent (three comparisons; OR, 0.94; 95% CI, 0.41-2.17). There was no between-study heterogeneity in any of these analyses. Overall, the random effects OR was 0.94 (95% CI, 0.75-1.18; no between-study heterogeneity) for the S versus L allele, 0.92 (95% CI, 0.63-1.35; P < 0.01 for heterogeneity) for the B versus b allele, and 1.03 (95% CI, 0.86-1.23; no between-study heterogeneity) for the f versus F allele. The meta-analysis shows that these four polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.     

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.     

Vitamin D receptor polymorphisms and risk of epithelial ovarian cancer

The vitamin D receptor (VDR) is a critical mediator of the cellular effects of vitamin D. The associations between four common VDR polymorphisms (BSMI, APAI, TAQI, and FOKI) and risk of epithelial ovarian cancer (EOC) were assessed in a case-control study nested within two prospective cohorts. One hundred seventy incident cases of EOC and 323 individually matched controls were genotyped. Overall, no associations were observed in genotype analyses. Haplotypes combining three SNPs in high linkage disequilibrium (BSMI, APAI, and TAQI) were also not associated with risk. These observations do not support a role for BSMI, APAI, TAQI, and FOKI polymorphisms in epithelial ovarian cancer in a predominantly Caucasian population.     

Androgen receptor and vitamin D receptor gene polymorphisms and prostate cancer risk

We study the CAG repeat region in exon 1 of the androgen receptor (AR) and the TaqI polymorphism in exon 9 of the vitamin D receptor (VDR) and the association with prostate cancer. 137 incidentally discovered, histologically verified prostate cancers were analysed for CAG repeat length in AR and genotype at the TaqI site of the VDR. 124 control subjects were analysed to determine the CAG repeat length and TaqI genotype determined for 176 control subjects. An unpaired t-test shows that the mean CAG repeat length was significantly (p<0.001) shorter among cases (20.1 repeats) compared with controls (22.5 repeats). Dividing the prostate cohort and controls into tertiles (< or = 19, 20-22, > or = 23 repeats) shows that short repeats are significantly more common among cases (odds ratio (OR) 4.45, p=0.00003). Genotype frequencies for the TaqI polymorphism reveals no significant differences between cases and controls. We conclude that men with a short CAG repeat in the androgen receptor gene have an increased risk of developing prostate cancer.     

Vitamin D receptor gene polymorphisms and epithelial ovarian cancer risk.

Epidemiologic and laboratory studies support a role for the vitamin D endocrine system in ovarian carcinogenesis. The association of ovarian cancer risk with polymorphisms in the vitamin D receptor (VDR) gene, including rs10735810 (FokI), rs11568820 (Cdx-2), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI), and BsmI-ApaI-TaqI combined genotypes, was examined among 313 women with epithelial ovarian carcinoma and 574 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. The associations of VDR polymorphisms with risk were generally inconsistent across ethnic groups. Among Caucasian women (72 cases, 148 controls), heterozygous and homozygous ApaI A allele carriers were at increased ovarian carcinoma risk compared with homozygous carriers of the ApaI a allele (OR 2.8, 95% CI 1.2-7.0 and OR 3.4, 95% CI 1.3-9.1; P(trend) = 0.02). Caucasian heterozygous carriers of FokI f allele were also at increased risk of ovarian carcinoma compared with homozygous carriers of the common allele (OR 2.5, 95% CI 1.3-4.8; P(trend) = 0.04). Among Japanese women (94 cases, 173 controls), ovarian cancer risk was significantly decreased (OR 0.5, 95% CI 0.3-0.9) among Cdx-2 A allele heterozygotes compared with homozygote G allele carriers (P(trend) = 0.03). Compared with the bbaaTT BsmI-ApaI-TaqI genotype, bbaATT and BBAAtt genotypes were associated with increased ovarian cancer risk in Caucasian women (OR 4.2, 95% CI 1.3-13.1 and OR 5.2, 95% CI 1.6-17.5), but not in Japanese women (OR 1.1, 95% CI 0.6-1.9 and OR 2.3, 95% CI:0.4-12.3). This investigation provides some evidence that polymorphisms in the VDR gene might influence ovarian cancer susceptibility.     

Vitamin D receptor genotypes/haplotypes and prostate cancer risk.

The vitamin D receptor (VDR) gene has been associated with prostate cancer, although previous results are somewhat equivocal. To further study this, we did a family-based case-control study (N = 918) of the association between prostate cancer and six common VDR variants: Cdx2, FokI, BsmI, ApaI, TaqI, and the poly-A microsatellite. Looking at each variant alone, only FokI and ApaI were associated with disease. The FokI FF genotype was inversely associated with prostate cancer among men with less advanced disease (i.e., Gleason score <7 and tumor stage 相似文献   

Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk

Introduction  

Vitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined.     

Vitamin D receptor polymorphisms and prognosis of patients with epithelial ovarian cancer

Background:

Recently, the vitamin D receptor (VDR) polymorphism FokI was shown to be associated with susceptibility to ovarian cancer. We aimed to examine whether VDR FokI polymorphisms influence the survivals of patients with epithelial ovarian cancer (EOC).

Methods:

VDR polymorphisms from FokI in 101 patients with EOC were genotyped by sequencing. Overall survival was compared between FokI single nucleotide polymorphism using Kaplan–Meier survival curves with log-rank tests and the Cox proportional hazard model adjusted for ages, stages, histology, and existence of residual tumour.

Results:

The FokI C/C genotypes were associated with better prognosis compared with the C/T and T/T genotypes (log-rank test: P=0.008; adjusted hazard ratio, 0.18; 95%CI 0.05–0.61; P=0.006).

Conclusions:

These results suggest that the VDR polymorphisms from the FokI genotype may be associated with improved prognosis of patients with EOC.     

Vitamin D receptor gene polymorphisms, insulin-like growth factors, and prostate cancer risk: a population-based case-control study in China

Operating through the vitamin D receptor (VDR), vitamin D inhibits prostate cancer growth and increases insulin-like growth factor binding protein (IGFBP) expression, suggesting that the vitamin D and insulin-like growth factor (IGF) regulatory systems may operate together to affect prostate cancer. Among 191 newly diagnosed prostate cancer cases and 304 randomly selected population controls in Shanghai, China, we found no significant association between the BsmI or FokI VDR gene polymorphisms and prostate cancer risk. However, we found that among men with the ff FokI genotype, those in the highest tertile of plasma IGFBP-3 had a decreased risk versus those in the lowest tertile (odds ratio, 0.14; 95% confidence interval, 0.04-0.56; P(trend) < 0.01), whereas among men with the FF and Ff genotypes, IGFBP-3 was not associated with risk. Similarly, IGFBP-1 was inversely associated with prostate cancer risk only among men with the ff FokI genotype (odds ratio, 0.25; 95% confidence interval, 0.07-0.85; P(trend) = 0.02). No such FokI genotype-specific effects were observed for IGF-I or IGF-II. Our findings in a low-risk population suggest that the IGF and vitamin D regulatory systems may interact to affect prostate cancer risk. Larger studies are needed to confirm these findings and clarify the underlying mechanisms.     

Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression.

Vitamin D plays an important role in cell growth and differentiation and is proposed to protect against cancer initiation and/or progression. The vitamin D receptor (VDR) has a thymine/cytosine (T/C) polymorphism located in the first of two potential start (ATG) codons that can be detected by a RFLP using the endonuclease FokI. The C variant, which lacks the first ATG, results in a shorter VDR and is referred to as the F allele. The T variant (f allele) initiates at the first ATG. We examined the association of the VDR FokI genotype with histopathological characteristics and prognosis of prostate cancer among 191 mostly Caucasian subjects who had undergone radical prostatectomy between 1984 and 1992. The frequencies of the FF, Ff, and ff genotypes were 41%, 38%, and 21%, respectively. Subjects with the ff genotype had a lower mean percentage of Gleason grade 4/5 cancer (30.3%) than subjects with the FF or Ff genotypes (42.8% and 43.8%, respectively; P = 0.015 by t test for ff versus FF + Ff). The data suggest that the 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. The age-adjusted risk of prostate-specific antigen failure was lower for the ff genotype than for the FF genotype by Cox proportional hazards analysis but did not achieve statistical significance (hazard ratio = 0.76; 95% confidence interval, 0.44-1.32). This risk reduction disappeared after further adjustment for percentage of Gleason grade 4/5, cancer volume, and preoperative serum prostate-specific antigen level (hazard ratio = 1.03; 95% confidence interval, 0.58-1.85). In conclusion, the ff genotype was associated with less aggressive histopathological findings than Ff or FF genotypes. Additional studies with a larger sample size and investigation of the functional significance of the FokI polymorphism in prostate cancer cells are warranted.     

Vitamin D receptor polymorphisms in patients with cutaneous melanoma

The vitamin D receptor (VDR) gene has been associated with cancer risk, but only a few polymorphisms have been studied in relation to melanoma risk and the results have been inconsistent. We examined 38 VDR gene single nucleotide polymorphisms (SNPs) in a large international multicenter population-based case-control study of melanoma. Buccal DNAs were obtained from 1,207 people with incident multiple primary melanoma and 2,469 with incident single primary melanoma. SNPs with known or suspected impact on VDR activity, haplotype tagging SNPs with ≥ 10% minor allele frequency in Caucasians, and SNPs reported as significant in other association studies were examined. Logistic regression was used to calculate the relative risks conferred by the individual SNP. Eight of 38 SNPs in the promoter, coding, and 3' gene regions were individually significantly associated with multiple primary melanoma after adjusting for covariates. The estimated increase in risk for individuals who were homozygous for the minor allele ranged from 25 to 33% for six polymorphisms: rs10875712 (odds ratios [OR] 1.28; 95% confidence interval (CI), 1.01-1.62), rs4760674 (OR 1.33; 95% CI, 1.06-1.67), rs7139166 (OR 1.26; 95%CI, 1.02-1.56), rs4516035 (OR 1.25; 95%CI, 1.01-1.55), rs11168287 (OR 1.27; 95%CI, 1.03-1.57) and rs1544410 (OR 1.30; 95%CI, 1.04-1.63); for two polymorphisms, homozygous carriers had a decreased risk: rs7305032 (OR 0.81; 95%CI 0.65-1.02) and rs7965281 (OR, 0.78; 95%CI, 0.62-0.99). We recognize the potential false positive findings because of multiple comparisons; however, the eight significant SNPs in our study outnumbered the two significant tests expected to occur by chance. The VDR may play a role in melanomagenesis.     

Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer

Substantial experimental evidence indicates that the hormonal form of vitamin D promotes the differentiation and inhibits the proliferation, invasiveness, and metastasis of human prostatic cancer cells. Results from epidemiologic studies of vitamin D status and/or vitamin D receptor (VDR) polymorphisms and prostate cancer risk have been mixed. We conducted a population-based, case-control study of advanced prostate cancer among men ages 40 to 79 years from the San Francisco Bay area. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-Hispanic White men (450 cases and 455 controls). Using a reflectometer, we measured constitutive skin pigmentation on the upper underarm (a sun-protected site) and facultative pigmentation on the forehead (a sun-exposed site) and calculated a sun exposure index from these measurements. Biospecimens were collected for 426 cases and 440 controls. Genotyping was done for VDR polymorphisms in the 5' regulatory region (Cdx-2), exon 2 (FokI), and the 3' region (TaqI and BglI). Reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.33-0.80] and high occupational outdoor activity (OR, 0.73; 95% CI, 0.48-1.11). Significant risk reductions with the high-activity alleles FokI FF or Ff, TaqI tt, and BglI BB genotypes and a nonsignificant reduction with Cdx-2 AG or AA genotype were observed in the presence of high sun exposure, with ORs ranging from 0.46 to 0.67. Our findings support the hypothesis that sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer.     

维生素D及其受体与乳腺癌

维生素D(VitD)和维生素D受体(VDR)除了人们所熟知生理功能外,近些年来还发现与肿瘤之间有密切关系.约80%的乳腺癌表达VitDR,体内体外实验证明VitD可以抑制乳腺癌细胞增殖,诱导凋亡.VitD的类似物有望成为一种新型的抗癌药物.     

Vitamin D in the prevention and treatment of prostate cancer.

Current approaches to the management of prostate cancer include surgery, radiation therapy, or hormonal manipulation either individually or in combination. With an increase in understanding of the etiology and natural history of prostate cancer, the influence of dietary factors on the disease is becoming more evident. There have been a number of studies in this regard that have demonstrated a relationship between prostate cancer and numerous dietary constituents including vitamins. The fat-soluble vitamins A and D have both been found to affect the growth of prostate cancer in preclinical experiments. Of the two, vitamin D has been the focus of greater attention in recent years, and there are indications that it may be useful both in the prevention and treatment of prostate cancer. This article reviews the current literature in this area to determine if treatment with vitamin D would be a viable management alternative for the patient described in the case study.     

Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States)

Objective: The purpose of this study was to determine whether vitamin D receptor (VDR) gene polymorphisms influence risk of colorectal adenoma. Methods: Polymorphisms in the 5 and 3 ends of the VDR gene were genotyped for 373 colorectal adenoma cases and 394 controls. Results: Overall, there was no significant association between the 5 (FokI) or the 3 (BsmI) polymorphisms and adenoma risk. However, risk of large (>1 cm) adenomas decreased with increasing copies of the FokI f allele (p = 0.04). Compared to the FF genotype, odds ratios for the Ff and ff genotypes were 0.79 (95% CI 0.44–1.41) and 0.32 (95% CI 0.11–0.91), respectively. FokI genotype was more strongly related to large adenoma risk among subjects with low dietary calcium intake (OR_Ff = 0.48; 95% CI 0.17–1.3; OR_ff = 0.21; 95% CI 0.04–1.3), low dietary vitamin D intake (OR_Ff = 0.25; 95% CI 0.09–0.69; OR_ff = 0.22; 95% CI 0.04–1.2), or dark skin color (OR_Ff = 0.66; 95% CI 0.27–1.6; OR_ff = 0.10; 95% CI 0.01–1.0). Conclusion: These results suggest that VDR FokI genotype influences development of colorectal adenomas, and that the effect may be modified by calcium and vitamin D status.     

Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population.

There is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism Bsm I, an intronic 3' gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 (95% CI, 1.23-4.39). The Bsm I polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3' untranslated region. Thus, the 'L' poly (A) variant was also associated with a similar breast cancer risk. A 5' VDR gene variant, Fok I, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways.     

Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women

Introduction  

The involvement of vitamin D receptor (VDR), which is a key mediator in the vitamin D pathway, in breast cancer etiology has long been of interest.