Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common,inherited vitamin D-binding protein isoforms

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)—considered the best marker of total vitamin D exposure—is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (P_interaction = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P_interaction = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.     

Genetic sequence variants in vitamin D metabolism pathway genes,serum vitamin D level and outcome in head and neck cancer patients

Although some studies have reported associations between serum vitamin D level and prognosis in several cancers, others have found associations between genetic sequence variants (GSVs) in the vitamin D metabolism pathway genes and outcomes in various cancers including head and neck cancer (HNC). We comprehensively evaluated the association and interaction of GSVs in vitamin D metabolism pathway genes and their regulatory effects on circulatory serum vitamin D level in HNC outcome. We systemically evaluated the association of 89 tagging and candidate‐based GSVs in six major vitamin D metabolism pathway genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1 and CYP2R1) and the circulating serum vitamin D level with overall survival (OS) and second primary cancer (SPC) in 522 Stages I–II radiation‐treated patients with HNC. For OS: median follow‐up time was 8 years; for SPC, 4.4 years. The most common subsite was the larynx (84%). Three hundred and twelve patients were alive at the end of follow‐up for OS. SPCs were diagnosed in 108 patients and were primarily of lung (46%). Serum vitamin D levels were significantly lower in patients carrying the minor alleles of GC:rs4588 and CYP2R1:rs10500804. CYP24A1:rs2296241 was significantly associated with OS and CYP2R1:rs1993116 was with SPC. These two GSVs remained significantly associated after adjusting for serum vitamin D level and important clinical factors. GSVs in the vitamin D metabolism pathway genes were associated with disease outcomes in HNC patients; however, these GSVs are different from those affecting serum vitamin D levels.     

Serum Vitamin D Metabolites in Colorectal Cancer Patients Receiving Cholecalciferol Supplementation: Correlation with Polymorphisms in the Vitamin D Genes

Cholecalciferol (D₃) supplementation results in variable increases in serum 25(OH)D₃ levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D₃, 24,25(OH)₂D_3, 1,25(OH)₂D₃ and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D₃ supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D₃ supplementation. TagSNPs in CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR, and GC genes were genotyped in all patients, and the association between these SNPs and serum vitamin D₃ metabolites levels before and after D₃ supplementation was analyzed. The mean baseline serum 25(OH)D₃ level was less than 32 ng/mL in 65 % of the 313 CRC patients. In the 50 patients receiving D₃ supplementation, serum levels of 25(OH)D₃ increased (p?=?0.008), PTH decreased (p?=?0.036) and 24,25(OH)₂D₃, 1,25(OH)₂D₃, VDBP levels and PBMC 24-OHase activity were unchanged. GC SNP rs222016 was associated with high 25(OH)D₃ and 1,25(OH)₂D₃ levels at baseline while rs4588 and rs2282679 were associated with lower 25(OH)D₃ and 1,25(OH)₂D₃ levels both before and after D₃ supplementation. CYP2R1 rs12794714 and rs10500804 SNPs were significantly associated with low 25(OH)D₃ levels after supplementation but not with baseline 25(OH)D₃. Our results show that D₃ supplementation increased 25(OH)D₃ levels in all patients. GC rs4588 and rs2283679 SNPs were associated with increased risk of vitamin D₃ insufficiency and suboptimal increase in 25(OH)D₃ levels after D₃ supplementation. Individuals with these genotypes may require higher D₃ supplementation doses to achieve vitamin D₃ sufficiency.     

Serum 25(OH)D concentration,common variants of the VDR gene and lung cancer occurrence

The first aim of our study was to examine the association between common variants in VDR [rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), rs731236 (TaqI) and rs11568820 (Cdx2)] and lung cancer risk in the Polish population. Genotyping and statistical analysis which included Chi‐square test with Yates correction and haplotype frequency analysis were performed on a series of 840 consecutively collected lung cancer patients and 920 healthy controls. The second aim was to evaluate the link between serum 25(OH)D concentration and the number of lung cancers in a subgroup of 200 patients. A separate control group that consisted of 400 matched (by age, sex, smoking habits and the season of blood collection) healthy individuals was used to avoid posterior adjustment on the matched variables. Statistical analysis with the use of Chi‐square test with Yates was performed. We found no statistically significant difference in the distribution of the allels of studied VDR variants among cases and controls. A statistically significant over‐representation of VDR haplotypes: rs731236_A + rs1544410_T [odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.11–5.32, p < 0.001], rs731236_G + rs1544410_T (OR = 1.54, 95% CI = 1.31–1.81, p < 0.001) and rs731236_G + rs1544410_C (OR = 0.04, 95% CI = 0.03–0.07, p < 0.001) was detected. We found a tendency toward an increased number of lung cancers among individuals with low serum levels of 25(OH)D. To answer the question, whether VDR can be regarded as lung cancer susceptibility gene and low 25(OH)D serum levels is associated with lung cancer occurrences, additional, multicenter study needs to be performed.     

Circulating 25-hydroxyvitamin D,vitamin D binding protein and risk of advanced and lethal prostate cancer

We previously found that higher total 25-hydroxyvitamin D [25(OH)D] levels were associated with lower risk of lethal prostate cancer. However, the relationships of bioavailable 25(OH)D and vitamin D binding protein (VDBP) with risk of advanced and lethal prostate cancer are unclear. In a prospective case–control study of 156 pairs of advanced prostate cancer cases and controls, we directly measured prediagnostic circulating 25(OH)D and VDBP and calculated bioavailable 25(OH)D using a validated formula. We examined the association of bioavailable 25(OH)D and VDBP levels with risk of advanced and lethal prostate cancer and whether total 25(OH)D levels interacted with VDBP levels to affect the risk. Conditional logistic models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to total 25(OH)D (p_trend = 0.02), bioavailable 25(OH)D levels were not more strongly associated with risk of advanced prostate cancer (p_trend = 0.14). Although VDBP levels were not associated with risk of advanced prostate cancer (p_trend = 0.16), we observed an interaction between total 25(OH)D levels and VDBP levels in relation to risk of advanced prostate cancer (p_interaction = 0.03). Compared to those with total 25(OH)D levels below the median and VDBP levels above the median (at highest risk), men with both levels above the median had a multivariable-adjusted OR of 0.31 (95% CI, 0.15–0.65) for advanced prostate cancer. We observed similar results when we restricted the analyses to 116 lethal prostate cancer cases and their controls. Our data suggest that VDBP levels may modify the association between total 25(OH)D levels and risk of advanced and lethal prostate cancer.     

An exploratory analysis of common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome

Purpose

Experimental and epidemiological evidence shows a beneficial role of vitamin D in cancer. In vitro evidence is consistent with a similar protective function in glioma; however, no study has yet examined the potential role of vitamin D in glioma.

Methods

We evaluated the association between common genetic variants in the vitamin D pathway and glioma risk and patient outcome in 622 newly diagnosed glioma cases and 628 healthy controls enrolled in a clinic-based case–control study. Subjects were genotyped for 7 candidate and tagging single nucleotide polymorphisms in the vitamin D receptor and 8 additional variants in NADSYN1, GC, CYP24A1, CYP2R1, and C10ORF88 linked in genome-wide association studies to serum concentrations of vitamin D. Unconditional logistic regression was used to estimate age- and gender-adjusted odds ratios and 95?% confidence intervals for glioma risk according to vitamin D genotypes. Proportional hazards regression was used to estimate hazard ratios for glioma-related death among 320 patients diagnosed with high-grade tumors. P values were uncorrected for multiple comparisons.

Results

Risk of astrocytic tumors was associated with variant alleles in rs3829251 (NADSYN1), rs10741657 (CYP2R1), rs2228570 (Fok1, VDR), and rs731236 (Taq1, VDR). No risk associations were found among oligodendroglial tumors. Survival associations were observed according to variant status for rs1544410 (Bsm1, VDR) and rs6013897 (CYP24A1).

Conclusion

This exploratory analysis provides limited evidence of a role for genetic variation in vitamin D pathway genes with glioma risk and survival.     

Variation in the Vitamin D Receptor Gene is not Associated with Risk of Colorectal Cancer in the Czech Republic

Purpose

Increased levels of vitamin D may protect against colorectal cancer (CRC) development and recurrence. Accumulating epidemiologic evidence suggests these effects may be partly mediated by genetic variants of the vitamin D receptor (VDR) proposed to be associated with altered risk of CRC. We wished to determine if common VDR polymorphisms affected CRC risk in the Czech Republic, a homogenous European population with a high CRC incidence rate.

Methods

Frequencies of the common VDR gene polymorphisms rs2238136, rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI) were determined using allele-specific PCR in a case control analysis of a series of 754 CRC patients and 627 patients without malignant disease recruited from centers throughout the Czech Republic. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association between these variants and risk of CRC.

Results

None of the four polymorphisms tested had any significant effect on CRC risk. No significant differences were observed in susceptibility when the population was stratified by anatomical sub-site, sex, BMI, smoking, alcohol, or presence of polyps.

Conclusions

We conclude that common variation in the VDR gene had little effect on its own on predisposition to sporadic CRC in the Czech population.     

Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans

Purpose

Disparities in both colorectal cancer (CRC) incidence and survival impact African Americans (AAs) more than other US ethnic groups. Because vitamin D is thought to protect against CRC and AAs have lower serum vitamin D levels, genetic variants that modulate the levels of active hormone in the tissues could explain some of the cancer health disparity. Consequently, we hypothesized that genetic variants in vitamin D-related genes are associated with CRC risk.

Methods

To test this hypothesis, we studied 39 potentially functional single-nucleotide polymorphisms (SNPs) in eight genes (CYP2R1, CYP3A4, CYP24A1, CYP27A1, CYP27B1, GC, DHCR7, and VDR) in 961 AA CRC cases and 838 healthy AA controls from Chicago and North Carolina. We tested whether SNPs are associated with CRC incidence using logistic regression models to calculate p values, odds ratios, and 95 % confidence intervals. In the logistic regression, we used a log-additive genetic model and used age, gender, and percent West African ancestry, which we estimated with the program STRUCTURE, as covariates in the models.

Results

A nominally significant association was detected between CRC and the SNP rs12794714 in the vitamin D 25-hydroxylase gene CYP2R1 (p = 0.019), a SNP that has previously been associated with serum vitamin D levels. Two SNPs, rs16847024 in the GC gene and rs6022990 in the CYP24A1 gene, were nominally associated with left-sided CRC (p = 0.015 and p = 0.018, respectively).

Conclusions

Our results strongly suggest that genetic variation in vitamin D-related genes could affect CRC susceptibility in AAs.     

Vitamin D intake,vitamin D receptor polymorphisms,and breast cancer risk among women living in the southwestern U.S.

No studies of dietary vitamin D intake and vitamin D receptor (VDR) have been conducted comparing breast risk among Hispanic women and non-Hispanic white (NHW) women. We investigated the association between vitamin D intake and breast cancer in a population-based case–control study of 1,527 NHW and 791 Hispanic breast cancer cases diagnosed in 1999–2004 in Arizona, New Mexico, Utah, and Colorado, and 1,599 NHW and 922 Hispanic age-matched controls. Vitamin D intake was assessed using food frequency questionnaires, and associations with breast cancer were adjusted for age, ethnicity, state, education, body mass index, smoking, age at menarche, age at first birth, parity, hormone exposure, height, and physical activity using logistic regression. BsmI, Poly A and FokI vitamin D receptor (VDR) genotypes were also measured. Dietary vitamin D intake was positively associated with breast cancer (highest vs. lowest quartile (Q ₄ vs. Q ₁): odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.15–1.60; P _trend = 0.003), whereas vitamin D supplement use was inversely associated with breast cancer (10+ μg/day vs. none: OR = 0.79, 95% CI = 0.65–0.96, P _trend = 0.01). Similar patterns in risk were observed by ethnicity and menopausal status. Positive associations with dietary vitamin D intake and inverse associations with supplement use were observed for ER+/PR+ and ER−/PR− breast cancers, but not for ER+/PR− disease. BsmI genotype significantly modified the association between dietary vitamin D and breast cancer overall. Future research is needed to better understand potential differences in breast cancer risk by vitamin D source and hormone receptor status.     

Circulating 25‐hydroxyvitamin D,vitamin D‐binding protein and risk of prostate cancer

We recently reported a significant positive association between 25‐hydroxyvitamin D [25(OH)D], the accepted biomarker of vitamin D status, and prostate cancer risk. To further elucidate this association, we examined the influence of vitamin D‐binding protein (DBP), the primary transporter of vitamin D compounds in the circulation. Prediagnostic serum concentrations of DBP were assayed for 950 cases and 964 matched controls with existing 25(OH)D measurements within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention Study of Finnish men. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and statistical tests were two sided. Serum DBP modified the association between serum 25(OH)D and prostate cancer, with higher risk for elevated 25(OH)D levels observed primarily among men having DBP concentrations above the median (OR = 1.81, 95% CI: 1.18–2.79 for highest vs. lowest quintile, p‐trend = 0.001) compared to those with DBP below the median (OR = 1.22, 95% CI: 0.81–1.84, p‐trend 0.97; p‐interaction = 0.04). Serum DBP was not associated with prostate cancer risk overall (OR = 0.96, 95% CI: 0.70–1.33 for highest vs. lowest quintile); however, high serum DBP was associated with significantly decreased risk of prostate cancer in men with lower (<median) 25(OH)D concentrations (OR = 0.59, 95% CI: 0.38–0.90 for highest vs. lowest quintile, p‐trend = 0.003) and increased risk in men with higher 25(OH)D concentrations (OR = 1.47, 95% CI: 0.98–2.20, p‐trend 0.10, p‐interaction = 0.02). Our data suggest that the primary vitamin D carrier protein, DBP, modulates the impact of vitamin D status on prostate cancer.     

Vitamin D‐binding protein,circulating vitamin D and risk of renal cell carcinoma

Cell culture experiments suggest that vitamin D may inhibit renal carcinogenesis, but human studies of circulating 25‐hydroxyvitamin D [25(OH)D], the accepted measure of vitamin D status, and kidney cancer have been null. Limited research has examined the role of circulating vitamin D‐binding protein (DBP) in the association between 25(OH)D and disease risk, and it is unclear whether free 25(OH)D in circulation is a better measure of effective exposure, or if DBP may independently impact outcomes. We conducted a nested case–control analysis within the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) Study to examine whether circulating DBP concentration was prospectively associated with risk of renal cell carcinoma, and whether it modified the association with 25(OH)D. Renal cell carcinoma cases (n = 262) were matched 1:1 to controls on age (±1 year) and date of blood collection (± 30 days). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of renal cell carcinoma risk by quartiles of 25(OH)D, DBP and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Men with higher DBP concentrations were at significantly decreased risk of kidney cancer (Q4 vs. Q1: OR = 0.17, 95% CI = 0.08–0.33; p‐trend < 0.0001), a finding unchanged by adjustment for 25(OH)D. Although we observed no association with total 25(OH)D, we found slightly increased risk with higher levels of estimated free 25(OH)D [Q4 vs. Q1 of the 25(OH)D:DBP ratio, OR = 1.61, 95% CI = 0.95–2.73; p‐trend = 0.09]. The strong protective association observed between higher circulating DBP concentration and kidney cancer risk requires replication but suggests a vitamin D‐independent influence of DBP.     

The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin d status

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (P(trend) < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer.     

Predicted vitamin D status and colon cancer recurrence and mortality in CALGB 89803 (Alliance)

BackgroundObservational studies suggest that higher levels of 25-hydroxyvitamin D₃ (25(OH)D) are associated with a reduced risk of colorectal cancer and improved survival of colorectal cancer patients. However, the influence of vitamin D status on cancer recurrence and survival of patients with stage III colon cancer is unknown.Patients and methodsWe prospectively examined the influence of post-diagnosis predicted plasma 25(OH)D on outcome among 1016 patients with stage III colon cancer who were enrolled in a National Cancer Institute-sponsored adjuvant therapy trial (CALGB 89803). Predicted 25(OH)D scores were computed using validated regression models. We examined the influence of predicted 25(OH)D scores on cancer recurrence and mortality (disease-free survival; DFS) using Cox proportional hazards.ResultsPatients in the highest quintile of predicted 25(OH)D score had an adjusted hazard ratio (HR) for colon cancer recurrence or mortality (DFS) of 0.62 (95% confidence interval [CI], 0.44–0.86), compared with those in the lowest quintile (P_trend = 0.005). Higher predicted 25(OH)D score was also associated with a significant improvement in recurrence-free survival and overall survival (P_trend = 0.01 and 0.0004, respectively). The benefit associated with higher predicted 25(OH)D score appeared consistent across predictors of cancer outcome and strata of molecular tumor characteristics, including microsatellite instability and KRAS, BRAF, PIK3CA, and TP53 mutation status.ConclusionHigher predicted 25(OH)D levels after a diagnosis of stage III colon cancer may be associated with decreased recurrence and improved survival. Clinical trials assessing the benefit of vitamin D supplementation in the adjuvant setting are warranted.ClinicalTrials.gov IdentifierNCT00003835     

Inverse association between serum 25(OH) vitamin D levels and non-melanoma skin cancer in elderly men

To determine the relationship between 25(OH) vitamin D levels and non-melanoma skin cancer (NMSC), we performed a nested case–control study in ambulatory, elderly men enrolled in the Osteoporotic Fractures in Men (MrOS) Study. Health habit and medical history, including self-reported history of NMSC were recorded and 25(OH)D levels were measured on serum collected at baseline from a random sample of Caucasian MrOS subjects. Mean age (73 ± 5), BMI, daily vitamin D and calcium intake were similar in the men with (n = 178) and without NMSC (n = 930), but higher levels of 25(OH)D were associated with a decreased risk of having a history of NMSC (P _trend  = 0.04). Men in the highest quintile of 25(OH)D (>30 ng/mL) had 47% lower odds of NMSC (95% CI: 0.30–0.93, p = 0.026) compared to those in the lowest quintile. Our results suggest that a diagnosis of NMSC is not a surrogate for adequate 25(OH)D levels or increased UV exposure, and high 25(OH)D levels may be associated with a reduced risk of NMSC.     

Changes in vitamin D after gastrectomy

Background We previously reported that the administration of 1α hydroxy vitamin D3 was effective for treating post-gastrectomy bone disorders. Accordingly, we performed the present study to obtain evidence supporting the effectiveness of 1α hydroxy vitamin D3 in post-gastrectomy patients. Methods The study involved 22 outpatients who had undergone gastrectomy for gastric cancer and had not been treated with 1α hydroxy vitamin D3 or calcium. They comprised 17 men and 5 women, with a mean age of 61.9 years. Laboratory tests were performed to examine the following parameters: 1,25(OH)₂ vitamin D3; 25(OH) vitamin D3; 24,25(OH)₂ vitamin D3; ionized calcium; calcium; phosphorus; alkaline phosphatase; N-parathyroid hormone; and osteocalcin. Results The level of 1,25(OH)₂ vitamin D3, the most active of the vitamin D metabolites, was found to be normal in all of the patients. In contrast, the level of 25(OH) vitamin D3, which shows weak activity, was below the normal range in 7 of the 22 patients (31.8%). The mean serum level of 25(OH) vitamin D3 was significantly lower in patients at 1 year or more postoperatively than the level in those at less than 1 year postoperatively (P = 0.041), as well as being significantly lower in patients who had received total gastrectomy than in patients who underwent other gastrectomy procedures. The level of 24,25(OH)₂ vitamin D3, a metabolite of 25(OH) vitamin D3 that shows weak activity, was below the normal range in 19 of the 22 patients (86.4%). On multivariate analyses, factors associated with the change in vitamin D metabolites did not remain. Conclusion The patients showed a decrease of 25(OH) vitamin D3 and 24,25(OH)₂ vitamin D3, which are metabolites that show weak activity. This suggests that a homeostatic response maintains the normal level of 1,25(OH)₂ vitamin D3, which is important for calcium regulation. Thus, it was suggested that gastrectomy had a moderate influence on the metabolism of vitamin D. However we could not detect any factor associated with the decrease of 25(OH) vitamin D3 and 24,25(OH)₂ vitamin D3.     

A prospective study of aromatase inhibitor therapy,vitamin D,C-reactive protein and musculoskeletal symptoms

This study compared type, severity and location of musculoskeletal symptoms and associations with 25-hydroxyvitamin D (25(OH)D) and C-reactive protein (CRP) concentrations between women initiating aromatase inhibitor (AI) therapy and an unexposed comparison group. A 6-month prospective cohort study was conducted, enrolling 100 breast cancer patients prior to initiating AI treatment and an unexposed comparison group of 200 postmenopausal women. Multivariate associations were assessed with generalized linear models. At baseline, 55% of breast cancer patients and 63% of the comparison group reported any musculoskeletal symptoms. Among the unexposed group, prevalence and severity of symptoms remained constant with no statistically significant change over 6 months. Among breast cancer patients, but not unexposed women, the pain severity score significantly increased over the 6 month period for joint (P _trend < 0.001), muscle (P _trend = 0.004), and bone pain (P _trend = 0.01). Women treated with AIs were more likely to report pain in wrists/palms (63% at 6 months) compared to unexposed women (31% at 6 months) (P < 0.001). 25(OH)D concentrations increased over the study period among breast cancer patients (P _trend = 0.004). An increase in pain severity and prevalence was observed among breast cancer patients despite an increase in 25 (OH)D concentration. CRP concentrations were not associated with symptoms. Musculoskeletal symptoms are common among postmenopausal women. Breast cancer patients initiating AI treatment were at increased risk for developing new onset and more severe joint, muscle and bone pain compared to unexposed women, with a distinct distribution. AI-associated symptoms were not associated with 25(OH)D or CRP concentrations.     

Modification of the inverse association between dietary vitamin D intake and colorectal cancer risk by a FokI variant supports a chemoprotective action of Vitamin D intake mediated through VDR binding

Vitamin D has anticarcinogenic properties and might influence colorectal cancer (CRC) risk, but the epidemiological evidence is inconsistent. Many mechanisms of action for vitamin D have been proposed, with some of them initiating via its binding to the vitamin D receptor (VDR). Using a large Scottish case-control study, we investigated (i) main associations between CRC, vitamin D and calcium dietary intake and 4 VDR single nucleotide polymorphisms (rs10735810, rs1544410, rs11568820, rs7975232) and (ii) interaction associations between the VDR variants, vitamin D and calcium intakes. Inverse and dose-dependent associations were found between CRC risk, dietary [Odds ratio (OR) = 0.77, 95% confidence intervals (CI) 0.63, 0.92, p-trend = 0.012] and total vitamin D (OR = 0.80, 95% CI 0.65, 0.98, p-trend = 0.014) intake in multivariable-adjusted logistic regression models, whereas neither calcium intake nor any of the VDR variants were associated with CRC. Additionally, we observed statistically significant interactions (case-control, case-only designs) between vitamin D and calcium intake and rs10735810 (p-interaction 0.02, 0.006, respectively). We conducted meta-analyses of cohort, case-control and serum studies that also showed an inverse association between dietary vitamin D intake and CRC (serum studies: combined OR = 0.70, 95% CI 0.56, 0.87). The evidence of interaction we report here further supports the inverse association between vitamin D mediated through binding to the VDR.     

Association between Circulating Vitamin D,the Taq1 Vitamin D Receptor Gene Polymorphism and Colorectal Cancer Risk among Jordanians

Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form 1,25(OH)2D to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by pairedt-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancerpatients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT (8.91±4.31) and Tt (9.15±5.25) genotypescompared to control ((21.3±8.31) and (19.3±7.68); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.     

Associations of circulating retinol, vitamin E, and 1,25-dihydroxyvitamin D with prostate cancer diagnosis, stage, and grade

Purpose

Some epidemiological studies suggest that vitamin A (retinol), vitamin E, and vitamin D (total 25-hydroxyvitamin D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)₂D) are protective against prostate cancer. However, the evidence is not conclusive, with positive and null associations reported for all three vitamins. Limitations of previous studies include small sample size, lack of population controls, and reliance on self-reported dietary intake. Few studies have explored the interactions of circulating 25(OH)D with 1,25(OH)₂D or retinol, which are biologically plausible interactions.

Methods

We investigated the associations of circulating retinol, vitamin E, and 1,25(OH)₂D with PSA-detected prostate cancer risk, stage, and grade in a case–control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. We investigated the possibility of an interaction between 25(OH)D and 1,25(OH)₂D and whether the previously observed association between 25(OH)D and prostate cancer may be modified by retinol levels.

Results

We included 1,433 prostate cancer cases and 1,433 healthy controls. There was no evidence of associations of circulating retinol, vitamin E, or 1,25(OH)₂D with overall prostate cancer risk, stage (advanced vs localized), or Gleason grade (high- (≥7) vs low (<7) grade). There was no evidence of an interaction of 1,25(OH)₂D and 25(OH)D with prostate cancer risk, stage, or grade (p interaction ≥ 0.24). The association between 25(OH)D and prostate cancer did not differ by retinol level (p interaction?=?0.34).

Conclusions

We found no evidence that retinol, vitamin E, or 1,25(OH)₂D concentrations were associated with overall prostate cancer risk or more aggressive prostate cancer phenotypes. There was no evidence of an interaction between 25(OH)D and 1,25(OH)₂D or retinol.     

Racial disparity in death from colorectal cancer

BACKGROUND:

The reasons blacks have higher mortality rates from colorectal cancer (CRC) than non‐Hispanic whites are not fully understood. Blacks have higher rates of vitamin D deficiency than non‐Hispanic whites, and vitamin D deficiency has been associated with CRC. The authors of this report investigated the association of vitamin D deficiency with excess risk for CRC mortality for blacks in the Third National Health and Nutrition Examination Survey (NHANES III) that was conducted from 1988 to 1994.

METHODS:

The association between serum 25(OH)D levels and CRC mortality and its contribution to elevated risk among blacks were studied using baseline data from NHANES III and CRC mortality data through 2006 from the National Death Index. By using survival models, the adjusted risk of death from CRC for African Americans was examined with and without adjusting for vitamin D deficiency, which was defined as an 25(OH)D level <20 ng/dL.

RESULTS:

Black race (hazard ratio [HR], 2.03; 95% confidence interval [95% CI], 1.04‐3.95), age (HR, 1.12; 95% CI, 1.09‐1.15), not having health insurance (HR, 2.45; 95% CI, 1.12‐5.36), and a history of CRC (HR, 7.22; 95% CI, 2.12‐24.6) predicted CRC mortality. When added to the model, vitamin D deficiency was associated significantly with CRC mortality (HR, 2.11; 95% CI, 1.11‐4.00), and the effect of race was decreased (HR, 1.60; 95% CI, 0.87‐2.93); the 40% attenuation was statistically significant (F_1,49 = 4.85; P = .03). Similar results were observed when participants who had a history of CRC were excluded from the analysis.

CONCLUSIONS:

The current findings were consistent with the hypothesis that vitamin D deficiency contributes to excess African‐American mortality from CRC. Cancer 2011. © 2010 American Cancer Society.