Vitamin D receptor polymorphism and prostate cancer prognosis

BackgroundProstatic epithelial cells synthesize the active form of vitamin D (1,25-dihydroxyvitamin D₃), which participates in regulating prostate growth. Calcitriol, a synthetic form of vitamin D₃, exhibits antiproliferative and prodifferentiation activities in prostate cancer. The function of 1,25-dihydroxyvitamin D₃ is mediated by its binding to vitamin D receptor (VDR). VDR forms a heterodimer, typically with retinoid X receptor, to regulate vitamin D target genes. We evaluated the relationship between VDR polymorphism and clinical characteristics associated with prostate cancer risk and prognosis among Egyptian men.Materials and methodsThis case-control study included 2 groups of patients: group A, a control group of 50 subjects with benign prostate hyperplasia, and group B, 50 subjects newly diagnosed with prostate cancer. All participants performed complete blood count, liver and kidney function tests, prostate specific antigen measurement, histopathological analysis and immunohistochemistry for Dickkopf Homolog 3. Restriction fragment length polymorphism-polymerase chain reaction as performed to detect VDR polymorphism.ResultsPatients with prostate cancer and controls showed a significantly different CA genotype frequency (p = 0.007). Furthermore, prostate-specific antigen levels were significantly different in different genotypes in patients with prostate cancer (p < 0.001). Finally, T stage and the VDR ApaI C/A polymorphism were significantly associated (p < 0.041).ConclusionThe VDR ApaI C/A polymorphism may be a diagnostic and prognostic marker for prostate cancer in Egyptian men.     

Vitamin D and prostate cancer

Current approaches to the management of prostate cancer include surgery, radiation therapy or hormonal manipulation either individually or in combination. Diet is increasingly being recognized as playing a role in many cancers including that of the prostate. There is now considerable evidence suggesting a role for vitamin D in prostate cancer. In this article, we have reviewed the current evidence supporting the use of vitamin D in the prevention and treatment of prostate cancer.     

Vitamin D and prostate cancer.

The original hypothesis of Schwartz and Hulka (1990) proposing that vitamin D deficiency may be a risk factor for prostate cancer has triggered many studies. Epidemiological studies have supported this hypothesis with findings that sunlight exposure is inversely proportional to prostate cancer mortality and that prostate cancer risk is greater in men with lower levels of vitamin D (Hanchette and Schwartz, 1992; Corder et al, 1993; Ahonen et al, 2000). Prostate cancer cells express receptors for 1,25(OH)2D3 and some cell lines are growth inhibited when treated with 1,25(OH)2D3 (reviewed in Blutt and Weigel, 1999). The mechanism of action of these growth inhibitory effects of 1,25(OH)2D3 in LNCaP cells involves G1 accumulation, induction of quiescence, and an increase in apoptosis of the cancer cells (Blutt et al, 1997, 2000a; Zhuang and Burnstein, 1998). In vivo, 1,25(OH)2D3 and its analogs slow tumor growth and hinder metastasis of prostate tumors in rodent models (Schwartz et al, 1995; Getzenberg et al, 1997; Lokeshwar et al, 1999; Blutt et al, 2000b), and 1,25(OH)2D3 may have clinically relevant effects (Gross et al, 1998). More work is required to elucidate the mechanism of 1,25(OH)2D3 action in prostate cancer cells and to identify optimal 1,25(OH)2D3 analogs in a search for compounds with a better separation of growth inhibitory effects from hypercalcemic effects.     

Vitamin D and prostate cancer risk.

Prostate cancer is a progressive, multistep disease which presents many stages for intervention. Microscopic cancer is found in the prostate beginning by age 30 in about 20% of men, and the incidence increases steadily so that by the time a man is 90 years old, he has almost a 100% chance of having cancer in his prostate. Independent, multiple foci of cancer are present in the majority of prostate specimens, and the incidence of premalignant lesions is even higher than that of cancer. Yet, despite the high incidence of microscopic cancer, only 8% of men in the US present with clinically significant disease during their lifetime. Furthermore, only 3% of men in the US die of prostate cancer. In no other human cancer is there such disparity between the high incidence of microscopic malignancy and the relatively low death rate. Thus, there are many windows of opportunity for control of prostate cancer. Evidence from diverse areas of study - epidemiologic, molecular, genetic, cellular, animal models, and clinical trials - suggests that vitamin D may be an effective preventive agent against prostate cancer.     

Vitamin D and the epidemiology of prostate cancer

Mortality rates from prostate cancer are significantly higher among African Americans than Caucasian Americans and are inversely related to the availability of ultraviolet (UV) radiation. These findings support the hypothesis, originally proposed in 1990, that prostate cancer may be caused by vitamin D deficiency. In 1992, specific receptors for 1,25-dihydroxyvitamin D [1,25(OH)2D] were demonstrated in human prostate cells. We and others have shown that 1,25(OH)2D exerts prodifferentiating, antiproliferative, and antimetastatic effects on these cells. In 1998 we demonstrated that normal prostate cells express 1alpha-hydroxylase and synthesize their own 1,25(OH)2D. Thus, 1,25(OH)2D is an autocrine hormone in the prostate. The consensus emerging from analytic epidemiologic studies is that low levels of UV radiation/vitamin D are indeed associated with an increased risk of prostate cancer in individual men. The evolution of our understanding of the role of vitamin D in the epidemiology of prostate cancer parallels our understanding of the role of vitamin D in the epidemiology of rickets. In both diseases, ecologic observations about UV radiation preceded experimental observations and were subsequently validated by them.     

Body mass index and the risk of abdominal hernia: a Mendelian randomization study

Hernia - Abdominal hernia (AH) is one of the most common clinical diseases. A large number of observational studies have found that obesity is an important risk factor for AH. However, the causal...     

Vitamin D receptor gene polymorphisms and prostate cancer risk

BACKGROUND: Vitamin D is a steroid hormone that is thought to play a role in the etiology and progression of prostate cancer. Hormone activity requires binding to the vitamin D receptor (VDR), which contains several genetic polymorphisms that have been associated with risk of prostate cancer. To further evaluate this relationship, we conducted a population-based case-control study of the VDR BsmI, FokI, and Poly-A polymorphisms, and prostate cancer. METHODS: Germline DNA samples and survey data from incident prostate cancer cases (n = 559) and controls (n = 523) of similar age (40-64 years) without a history of the disease who resided in King County, Washington were analyzed. RESULTS: The frequency of the BsmI, FokI, and Poly-A genotypes were similar in cases and controls, and no overall association between any variants and prostate cancer risk were noted. Stratification by clinical features of disease revealed that among men with localized stage disease, the BsmI bb genotype was associated with a modest increase in risk (OR, 1.49; 95% CI, 1.02-2.17; P = 0.04) compared to the BB genotype. CONCLUSIONS: These results suggest that polymorphisms in the VDR gene are not strong predictors of prostate cancer risk among Caucasian men in the U.S.     

Vitamin D receptor gene polymorphism and prostate cancer risk

BACKGROUND: 1,25-dihydroxyvitamin D, the active form of vitamin D, exerts antiproliferative effect on prostatic cells, mediated through the vitamin D receptor. In a case-control study, we examined whether the vitamin D receptor (VDR) gene polymorphism in exon 9 could affect prostate cancer susceptibility. METHODS: One hundred ninety newly diagnosed prostate cancer patients and 190 age-matched men with benign prostatic hyperplasia (BPH), in whom the presence of prostate cancer was excluded clinically or histologically, were recruited for this study. The VDR TaqI polymorphism was investigated by polymerase chain reaction (PCR) following restriction fragment length polymorphism using DNA from lymphocytes. Depending on the presence or absence of the TaqI restriction site at the third position of codon 352, patients were classified as TT, Tt, or tt. RESULTS: The frequency of the tt genotype was not significantly different between prostate cancer patients (18%) and controls (12%; P = 0.07). The odds ratio (OR), calculated relative to individuals with the TT genotype was 1.76 (95% confidence limit (CL) = 0.90-3.45). After stratification for Gleason score and prostate specific antigen levels in a case-case comparison (n = 190), no significant associations with the VDR genotypes were detectable either. CONCLUSIONS: In this case-control study of Austrian Caucasians, no statistically significant association of the VDR TaqI polymorphism and prostate cancer risk was found.     

Vitamin D deficiency and insufficiency among patients with prostate cancer

OBJECTIVE

To assess the frequency of vitamin D deficiency among men with prostate cancer, as considerable epidemiological, in vitro, in vivo and clinical data support an association between vitamin D deficiency and prostate cancer outcome.

PATIENTS, SUBJECTS AND METHODS

The study included 120 ambulatory men with recurrent prostate cancer and 50 with clinically localized prostate cancer who were evaluated and serum samples assayed for 25‐OH vitamin D levels. Then 100 controls (both sexes), matched for age and season of serum sample, were chosen from a prospective serum banking protocol. The relationship between age, body mass index, disease stage, Eastern Cooperative Oncology Group performance status, season and previous therapy on vitamin D status were evaluated using univariate and multivariate analyses.

RESULTS

The mean 25‐OH vitamin D level was 25.9 ng/mL in those with recurrent disease, 27.5 ng/mL in men with clinically localized prostate cancer and 24.5 ng/mL in controls. The frequency of vitamin D deficiency (<20 ng/mL) and insufficiency (20–31 ng/mL) was 40% and 32% in men with recurrent prostate; 28% had vitamin D levels that were normal (32–100 ng/mL). Among men with localized prostate cancer, 18% were deficient, 50% were insufficient and 32% were normal. Among controls, 31% were deficient, 40% were insufficient and 29% were normal. Metastatic disease (P = 0.005) and season of blood sampling (winter/spring; P = 0.01) were associated with vitamin D deficiency in patients with prostate cancer, while age, race, performance status and body mass index were not.

CONCLUSIONS

Vitamin D deficiency and insufficiency were common among men with prostate cancer and apparently normal controls in the western New York region.     

Vitamin D receptor gene polymorphism in familial prostate cancer in a Japanese population

AIM: Vitamin D acts as an antiproliferative agent against prostate cells. Epidemiological study has shown that a low level of serum vitamin D concentration is a risk factor for prostate cancer. Vitamin D acts via vitamin D receptor (VDR), and an association of genetic polymorphisms of the VDR gene has been reported. In the current study, we examined the association of VDR gene polymorphisms with familial prostate cancer in a Japanese population. METHODS: We performed a case-control study consisting of 81 familial prostate cancer cases and 105 normal control subjects. Three genetic polymorphisms (BsmI, ApaI and TaqI) in the VDR gene were examined by the restriction fragment restriction length polymorphism method. RESULTS: Overall, there was no significant association of the VDR gene polymorphisms with familial prostate cancer risk in the cases and control subjects. However, a weak association between BsmI or TaqI genotypes and cancer risk was observed in subjects under 70 years of age. Stratification of cases by clinical stage or pathological grade did not show significant association between the VDR gene polymorphisms and prostate cancer risk. CONCLUSION: In the present study, we could not confirm any significant association between VDR gene polymorphisms with familial prostate cancer risk in a Japanese population. Further large-scale case-control studies are warranted to confirm the importance of VDR gene polymorphisms in familial prostate cancer.     

Causal effect of education on type 2 diabetes: A network Mendelian randomization study

BACKGROUNDThe causality between education and type 2 diabetes (T2DM) remains unclear.AIMTo identify the causality between education and T2DM and the potential metabolic risk factors [coronary heart disease (CHD), total cholesterol, low-density lipoprotein, triglycerides (TG), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fasting insulin, fasting glucose, and glycated hemoglobin] from summarized genome-wide association study (GWAS) data used a network Mendelian randomization (MR). METHODSTwo-sample MR and network MR were performed to obtain the causality between education-T2DM, education-mediator, and mediator-T2DM. Summary statistics from the Social Science Genetic Association Consortium (discovery data) and Neale Lab consortium (replication data) were used for education and DIAGRAMplusMetabochip for T2DM. RESULTSThe odds ratio for T2DM was 0.392 (95%CI: 0.263-0.583) per standard deviation increase (3.6 years) in education by the inverse variance weighted method, without heterogeneity or horizontal pleiotropy. Education was genetically associated with CHD, TG, BMI, WC, and WHR in the discovery phase, yet only the results for CHD, BMI, and WC were replicated in the replication data. Moreover, BMI was genetically associated with T2DM. CONCLUSIONShort education was found to be associated with an increased T2DM risk. BMI might serve as a potential mediator between them.     

维生素D在治疗激素非依赖性前列腺癌中的应用

维生素D的活性代谢物骨化三醇具有抗前列腺癌细胞生长作用。其机制包括抑制肿瘤细胞增殖、介导GI期细胞阻滞、介导凋亡、减少肿瘤细胞浸润和肿瘤血管形成。骨化三醇和一些抗癌药物、细胞毒药物、地塞米松等药物合用有协同抗癌效果,毒副作用小。一些骨化三醇类似物同样具有抗癌作用,且活性更强。