The Role of Vitamin D in Cancer Prevention

Acknowledgements

How Vitamin D Reduces the Risk of Cancer

Vitamin d and ovarian cancer studies

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Prior studies have suggested that vitamin D may reduce ovarian cancer risk. Thus, we examined whether three single nucleotide polymorphisms SNP in the vitamin D receptor VDR gene Fok1, Bsm1, Cdx2 were associated with risk of epithelial ovarian cancer in a retrospective case-control study New England Case-Control study, NECC and a nested case-control study of three vitamin d and ovarian cancer studies cohort studies: Data from the cohort studies were combined and analyzed using conditional logistic regression and pooled with the results from the NECC, which were analyzed using unconditional logistic regression, using a random effects model.

We obtained genotype data for 1, cases and 2, controls. The odds ratio OR for the ff versus FF genotype was 1. Among the prospective studies, the risk of ovarian cancer by plasma vitamin D levels did not clearly vary by any of the genotypes. Our results of an association with the Fok1 VDR polymorphism further support a role of the vitamin D pathway in ovarian carcinogenesis. Experimental and epidemiologic studies have suggested that vitamin D may be involved in the etiology of ovarian cancer.

The vitamin D receptor VDR is weakly to moderately expressed in normal ovarian cells but is more strongly expressed in ovarian cancer cell lines and tumor tissue 1 5. In vitro studies have reported that vitamin D administration inhibited cell growth and induced apoptosis in a dose-dependent manner in both animal 6 and human ovarian cancer cell lines 237 UV-B exposure, which initiates vitamin D production in the skin, has been inversely associated with ovarian cancer mortality in ecologic studies 13 Recently, vitamin d and ovarian cancer studies, we reported that plasma concentrations of hydroxyvitamin D a measure of overall vitamin D status and 1,dihydroxyvitamin D the biologically active but more tightly regulated form were not associated with risk of epithelial ovarian cancer overall in a prospective study However, hydroxyvitamin D levels were significantly inversely associated with ovarian cancer risk among overweight and obese women, possibly because vitamin D is fat soluble.

The VDR is a vitamin d and ovarian cancer studies component of the vitamin D pathway and a number of common single nucleotide polymorphisms SNP have been identified in this gene We focused on three SNPs that either have been associated with ovarian cancer risk in prior studies 2122 or have some known or hypothesized functional effect The study populations and case-control selections are described below.

Participants were enrolled in the study in 2 phases, from to cases, controls and from to cases, controls. Recruitment methods and eligibility criteria are described elsewhere Controls were identified using random digit dialing, license records, and town resident lists and were frequency matched to cases by age and state.

Additional details of the control selection have been published previously DNA was available for 1, cases and 1, controls for this analysis. The NHS cohort was established in amongU. Women in both cohorts completed an initial questionnaire and have been followed biennially by questionnaire to update exposure status and disease diagnoses.

In to32, NHS participants provided a blood sample and completed a short questionnaire Briefly, women arranged to have their blood drawn and shipped with an icepack, via overnight courier, to our laboratory where it was processed. In to33, additional women provided a buccal cell specimen using a mouthwash protocol, vitamin d and ovarian cancer studies.

We extracted DNA from each specimen within 1 wk of shingles and type 1 diabetes. Between to29, NHSII participants provided blood samples and completed a short questionnaire Collection methods were similar to those in the NHS. The WHS is a completed randomized trial examining low-dose aspirin and vitamin E supplementation for the primary prevention of cancer and cardiovascular disease that was initiated in 26 Citrate and EDTA blood samples were collected from 28, women before randomization.

We included women from the treatment and placebo groups. Prevalent and incident cases were similar on stage, histology, and survival time median survival, incident, 58 mo; prevalent, 80 mo; ref.

Additional details on the control selection have been published previously Laboratory personnel were blinded to case-control status, and each plate included blinded replicate samples for quality control purposes. Genotyping failures were considered missing data. Case-control sets and samples from the same study were assayed together and labeled to mask case-control status.

Because the NECC is a case-control study, these analyses were conducted separately from the cohort studies. The two resulting estimates were then combined using a random effects model to obtain pooled effect estimates We considered multiple a priori potential confounders and included those that changed the risk estimates or were very strong ovarian cancer risk factors in the final model for genetic analyses: Other vitamin d and ovarian cancer studies confounders such as body mass index BMItubal ligation, and smoking did not substantially change risk estimates and therefore were not included in the final model.

We additionally adjusted for age and study center in the NECC, as these were frequency matching variables. We calculated the P for trend for each unit increase in the number of minor alleles log-additive model using the Wald test. Our primary analysis included both invasive and borderline cases. However, in secondary analyses, we evaluated genetic associations among histologic subtypes of cases all invasive, serous invasive, serous borderline, endometrioid, vitamin d and ovarian cancer studies, and mucinous.

Multiplicative interaction terms between the above strata and genotypes homozygous wild-type versus heterozygous and homozygous variant were used to determine the P heterogeneity. We also examined statistical interactions between the SNPs. These analyses used unconditional logistic regression for both the cohort and case-control studies, additionally adjusting the cohort analysis for the matching factors and study. Furthermore, we examined the relationship between plasma vitamin D levels and ovarian cancer risk in prospectively collected cases and their matched controls in the three cohort studies.

Outliers 32 were identified separately by sample type and set to missing using methods described vitamin d and ovarian cancer studies Women in the NECC ranged in age from 16 to 77 years mean, 51 years at study entry. The characteristics of the NECC population have been described previously Overall, the risk factor distributions were as expected within each study; NHSII women were on average younger and had a longer duration of oral contraceptive use than women in the NHS.

Review of the screen shots for these plates revealed appropriate clustering, thus this finding is likely due to chance. The minor allele frequencies across the four studies were 0. The pooled OR comparing women with the ff versus FF genotype was 1. The corresponding, pooled OR for serous invasive cases was 1.

Neither the Bsm1 or Cdx2 polymorphisms were statistically significantly associated with overall ovarian cancer risk in study-specific or pooled analyses Table 2.

Results were similar among invasive cases only and by histologic subtype for the Bsm1 polymorphism data not shown. There was vitamin d and ovarian cancer studies modest positive association between the number of B alleles and risk among never users OR BB versus bb, vitamin d and ovarian cancer studies, 1. We further examined whether there was a combined effect of multiple SNPs on ovarian cancer risk.

Compared with the reference group of FF and GG, respectively, women with any other genotype were at a statistically significantly increased risk of ovarian cancer in the pooled analysis, vitamin d and ovarian cancer studies.

There were incident cases and matched controls with both genotype and plasma data in the three prospective cohort studies, vitamin d and ovarian cancer studies. We examined whether the association between plasma vitamin D concentrations differed by VDR genotype Table 3, vitamin d and ovarian cancer studies.

To our knowledge, this is the largest ovarian cancer study to examine the association between SNPs in the VDR gene and risk, and it is the first study to examine whether these SNPs modify the association of plasma hydroxy and 1,dihydroxyvitamin D levels with risk. Overall, our results suggest that the Fok1 but not the Bsm1 and Cdx2, polymorphism is associated with ovarian cancer risk.

Furthermore, the combined Fok1 and Cdx2 genotype may be important as well, although additional vitamin d and ovarian cancer studies are needed to confirm a potential interrelationship. In general, the association with plasma vitamin D levels did not vary by VDR genotype, suggesting that these two factors may act independently.

A second study 21using a nested case-control design among 2 cohort studies, did not observe any associations risperdal and caffeine the Fok1 relative risk [ RR ff versus FF, 1. In a meta-analysis of the current cohort and case-control studies plus the 2 prior studies, the summary OR comparing women with the Fok1 ff versus FF allele was 1. The summary OR is 1. We observed that the association of the Bsm1 VDR SNP with risk differed by oral contraceptive use history; however, the log-additive Bsm1 associations were not statistically significant in either never or ever users.

The two prior studies did not examine interactions by oral contraceptive use 21 There are some data supporting a potential reactive arthritis and doxycycline relationship between the vitamin D pathway and oral contraceptive use. Among premenopausal women, current oral contraceptive use is associated with higher vitamin D levels in Caucasians and African-Americans, and levels decline after women stop using oral contraceptives 33 In addition, a small randomized trial of oral contraceptive use in premenopausal women observed changes in bone metabolism after 3 months only among the intervention group who had the Bsm1 BB and Bb genotypes However, further research is needed to replicate this association and elucidate the underlying biological mechanisms.

We also observed a nearly statistically significant interaction between the Fok1 and Cdx2 genotypes, such that women with the FF and GG genotypes, vitamin d and ovarian cancer studies, respectively, had the lowest risk of cancer.

Prior studies have not examined this combination of genotypes 21 ; thus, it will be important to examine this potential interaction in larger studies. Our finding that the Fok1 f allele is associated with an increased risk of ovarian cancer is consistent with functional data on the Fok1 SNP. The variant f allele has an earlier start codon, leading to a protein with three extra amino acids that is less transcriptionally active and has a lower transactivation of VDR target genes than the F allele 2036 Furthermore, the variant protein may have a decreased capacity to inhibit cellular growth after administration of vitamin D This suggests that women with the f allele have a less active VDR, which may increase their ovarian cancer risk.

However, this potential functional effect may not be important in ovarian cancer carcinogenesis, given that we did not observe an association between this SNP and either risk of ovarian cancer or circulating vitamin D levels. These studies also observed that the A allele was associated with increased VDR expression in intestinal cells and enhanced calcium absorption.

To our knowledge, no functional percentage of population on anti depressants have examined a potential biological interplay between the Fok1 and Cdx2 SNPs; however, such data could lend support to the interaction we observed with ovarian cancer risk.

Experimental data also support a role of the vitamin D pathway specifically in ovarian carcinogenesis. A number of studies have observed that 1,dihydroxyvitamin D inhibits ovarian cancer cell growth 2379 12 and increases apoptosis 8, vitamin d and ovarian cancer studies. High 1,dihydroxyvitamin D levels also can increase VDR expression in ovarian cancer cell lines 8. One study reported that hydroxyvitamin D slightly increased cell growth of ovarian cancer cells; however, this effect was reduced at higher concentrations of hydroxyvitamin D exposure Because ovarian tumor tissue expresses the VDR 1 5these data suggest in total that some ovarian tumors may have a functional vitamin D pathway that could potentially be a target for prevention or treatment.

Interestingly, we did not observe that the association of plasma vitamin D levels with ovarian cancer risk differed by VDR genotype; however, the sample size precluded detecting small to modest effects or comparing extreme ends of the vitamin D spectrum. Examining a potential interrelationship between VDR genotype and plasma vitamin D levels could be important, as it is possible that women with xpect-pe and blood pressure associated with a higher risk of ovarian cancer may benefit more from high plasma vitamin D levels.

Biological data support this hypothesis. Colin, and colleagues 38 reported that the Fok1 polymorphism in cultured peripheral blood mononuclear cells from postmenopausal women was associated with growth inhibition only at low, physiologic doses. They suggested that the polymorphism may be clinically relevant only among those with insufficient vitamin D levels. Further experimental and epidemiologic research is needed to elucidate these relationships. Our study has several limitations and strengths.

Citrate plasma can dilute specimens, thus lowering the measured concentrations 42although the levels were similar between the two studies when adjusting for the dilution factor

 

Vitamin d and ovarian cancer studies

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