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PubMedDate not supplied

Vitamin D receptor (VDR) expression is not a prognostic factor in cervical cancer.

BACKGROUND: The aim of this study was to analyze whether VDR status is a prognostic factor that may be of importance for the assessment of recurrence in cervical cancer. MATERIALS AND METHODS: VDR-, Ki-67- and p53-status were analyzed immunohistochemically in cervical cancer patients (n=50) and in benign cervical tissue (n=15). The histopathological data of the tumours were evaluated. RNA was extracted from normal cervical tissue (n=4) and cervical carcinomas (n=8) using the method of Chomczynski. RNA was reverse-transcribed and RNA-levels were semiquantitatively detected by PCR. RESULTS: The expression of VDR was significantly increased in cervical cancer compared to normal cervical tissue on the protein-level but not on the RNA-level. No statistically significant correlations were found comparing VDR status with histopathological data (tumour stage, lymph node status, grading, histological tumour type), with the expression of the proliferation marker Ki-67 and of the tumour suppressor gene p53. CONCLUSION: Our findings indicate that VDR protein expression is not a prognostic factor in cervical cancer. The strong I/DR immunoreactivity that we observed in cervical cancer specimens supports the body of evidence that cervical cancer may be a target for therapeutically applied vitamin D analogues.

Adenocarcinoma↗
PubMedDate not supplied

Vitamin D receptor (VDR) expression is not a prognostic factor in breast cancer.

Breast cancer is characterized by its early haematogenous dissemination. Current modalities of risk assessment in lymph node-negative patients, to determine which patients should receive adjuvant chemotherapy, are not effective. The aim of this study was to analyze whether vitamin D receptor (VDR) status is a prognostic factor that may be of importance for the assessment of recurrence in breast cancer. VDR expression was analyzed immunohistochemically in breast cancer patients (n=228). No statistically significant correlations were found comparing VDR expression with histopathological data (tumor stage, lymph node status, grading, histological tumor type), with the expression of estrogen receptors (ER) or progesterone receptors (PR), with the proliferation marker Ki-67, with the tumor suppressor gene p53 or with the S-phase index. Our findings indicate that VDR protein expression is not a prognostic factor in breast cancer. The strong VDR immunoreactivity that we observed in breast cancer specimens supports the body of evidence that breast cancer may be a target for therapeutically applied vitamin D analogues.

Breast Neoplasms↗
PubMed2002

1,25(OH)2-vitamin D3 induces translocation of the vitamin D receptor (VDR) to the plasma membrane in skeletal muscle cells.

1,25-dihydroxy-vitamin D(3) (1,25(OH)(2)D(3)), the hormonally active form of vitamin D(3), acts through two different mechanisms. In addition to regulating gene expression via the specific intracellular vitamin D receptor (VDR), 1,25(OH)(2)D(3) induces rapid, non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. The activation of second messengers supports the hypothesis that a membrane-bound steroid receptor similar to those that mediate peptide hormone biology exists. Skeletal muscle is a target tissue for 1,25(OH)(2)D(3). Avian embryonic skeletal muscle cells (myoblasts/myotubes) have been shown to respond both genomically and non-genomically to the hormone. The present study provides evidence indicating that short-term treatment (1-10 min) with 1,25(OH)(2)D(3) induces translocation of the VDR from the nuclear to the microsomal fraction in chick myoblasts. This translocation is blocked by colchicine, genistein, or herbimycin, suggesting the involvement of microtubular transport and tyrosine kinase/s in the relocation of the receptor. By isolation of plasma membranes, it was demonstrated that the hormone increases the amounts of VDR specifically in this fraction. These results suggest that the nuclear VDR may be the receptor that mediates the non-genomic effects of 1,25(OH)(2)D(3) in chick myoblasts.

Animals↗
PubMed1999

VDR genotype and response to etidronate therapy in late postmenopausal women.

Twenty-four late postmenopausal women with osteoporosis were studied. The patients were separated in three subgroups according to the BsmI polymorphism of the vitamin D receptor (VDR) gene: BB (n = 8), Bb (n = 10) and bb (n = 6). They did not differ in age (mean ages were 66.0 years, 65.9 years and 63.9 years, respectively), years after menopause (18.7 years, 18.1 years and 18.4 years) or body weight (64.9 kg, 65.3 kg and 63.8 kg), the variables known to be associated with bone mineral density (BMD). The results show that the response to antiresorptive bisphosphonate therapy in combination with calcium supplementation is modified by VDR genotype. The lumbar spine BMD increased significantly faster in the BB and Bb groups (7.3% and 7.0%, respectively) compared with the bb group (2.5%) during 1 year of cyclic etidronate therapy (400 mg/day) and calcium supplementation (1000 mg/day). The biochemical marker of bone resorption (urinary hydroxyproline excretion) as well as the bone formation marker (serum levels of osteocalcin) decreased during the treatment. With respect to VDR genotype, a significantly higher decrease in osteocalcin level was observed in bb as compared with BB subjects. We conclude that the VDR genotype is involved in an individual's response to cyclic etidronate therapy with calcium supplementation.

Aged↗
PubMed2004

Simultaneous exposure of excess fluoride and calcium deficiency alters VDR, CaR, and calbindin D 9 k mRNA levels in rat duodenal mucosa.

Fluoride ingestion reduces intestinal calcium absorption; its molecular basis has not been studied. We studied the mRNA expression of calcium-sensing receptor (CaR), vitamin D receptor (VDR) and calbindin D 9 k (D 9 k) by northern blot analysis in the duodenal mucosa of rats. Weanling pups fed with chow diet containing adequate calcium (0.5% w/w) and drinking water (NaF < 1 ppm) served as controls (Group I) and were studied at 9 and 15 weeks. The pups, born to rats fed with a calcium-deficient diet (0.03%) and excess fluoride water (NaF 50 ppm), were continued on the same diet and water (Group II) until 9 weeks of age. Subsequently, Group II rats were divided into 4 subgroups; 3 subgroups with fluoride free water [II-A adequate calcium, II-B excess calcium (Ca 2%) and II-D calcium deficient], whereas II-C received fluorinated water and adequate calcium diet until 15 weeks. At 9 weeks, as compared to group-I, group-II had decreased VDR (P < 0.001) and D 9 k mRNA (P < 0.001), whereas CaR mRNA levels increased (P < 0.05). At 15 weeks, as compared to group-I, VDR mRNA further reduced in group II-D (P < 0.001) and II-C (P < 0.001), whereas it increased in group II-A. Removal of fluoride ingestion and calcium replenishment increased D 9 k mRNA expression, maximally in adequate calcium group (P < 0.001), while it was further reduced in group II-C (P < 0.001). CaR expression decreased significantly in all the groups. We conclude that excess fluoride reduces the mRNA levels of VDR and D 9 k in the duodenal mucosa of rats, thereby possibly reducing calcium absorption. Calcium supplementation with simultaneous fluoride removal improves their expression.

Animals↗
PubMed2006

Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type 2 diabetes patients.

Evidence exists that some clinical, metabolic and genetic risk factors are associated with the development of diabetic retinopathy (DR). The aim of the study was: (1) to define the prevalence of DR in the examined group of 267 patients with type 2 diabetes mellitus (T2DM) from a Polish population; (2) to identify in cross-sectional analysis, the clinical features associated with DR in the study group; and (3) to search for the association of 4 markers of vitamin D receptor (VDR), a candidate gene for vascular complications in diabetes, with DR. The examined group consisted of 146 female and 121 male T2DM patients (mean age at examination: 61.3+/-9.4 years; age at T2DM diagnosis: 50.0+/-9.2; T2DM duration: 11.3+/-7.8 years; body mass index (BMI): 30.5+/-5.5 kg/m(2); HbA1c: 7.8+/-1.5%). In all patients, the clinical and metabolic profile was determined. Diagnosis of DR was determined by a trained ophthalmologist by ophthalmoscopy after pupillary dilatation. Colour photographic documentation was made. The examined T2DM patients were genotyped for FokI, ApaI, BsmI and TaqI frequent VDR polymorphisms based on the restriction fragment length polymorphism method. The statistical analysis was performed using univariate and multivariate logistic regression (SAS) and haplotype analysis (Haplostat). DR was detected in 85 (31.8%) patients with T2DM. The multivariate analysis revealed that significant predictors of this complication were: never-smoking status (odds ratio 2.2, 95% confidence interval 1.2-4), urea serum level (1.3, 1.1-1.5), HbA1c level (1.4, 1.1-1.8) and insulin treatment (2.7, 1.4-5.1). Other features such as age of T2DM diagnosis, T2DM duration prior to ophthalmic exam, obesity (BMI>30), serum creatinine level, albumin/creatinine ratio and arterial hypertension were univariate predictors of DR, however they lost significance as independent predictors in multivariate analysis. Similarly, the alleles, genotypes, haplotype and haplotype combination of VDR were not associated with the examined complication. However, there was a suggestion of a possible slight association between the fbaT haplotype and DR (p=0.11). In conclusion, our study showed that DR in T2DM patients remains a frequent complication in Polish T2DM patients. We were able to confirm the role of some clinical risk factors, surprisingly including not-smoking status, as was previously shown in the UK Prospective Diabetes Study (UKPDS). VDR gene polymorphisms did not constitute a risk factor for this size of study group.

Body Mass Index↗
PubMed2005

The VDR, COL1A1, PTH, and PTHR1 gene polymorphisms are not associated with bone size and height in Chinese nuclear families.

We tested the relationship of the ApaI, Eco31I, BstBI, and (AAAG)n polymorphisms in the vitamin D receptor (VDR), collagen type I alpha-1 (COL1A1), parathyroid hormone (PTH), and parathyroid hormone (PTH)/PTH-related peptide receptor (PTHR1) genes with variations in bone size (BS) and height. Population stratification, total-family association, and within-family association were used to test these relationships in 400 Chinese nuclear families with a total of 1256 individuals. The BS at hip and spine was measured using a Hologic QDR 2000 dual-energy X-ray absorptiometry (DXA) scanner. The minor allele frequencies were 29.2%, 36.0%, and 14.0% for the VDR-ApaI, COL1A1-Eco31I, and PTH-BstBI markers, respectively. (AAAG)5 and (AAAG)6 of the PTHR1 gene are two major alleles in the Chinese people. Significant population stratification was found between the spine BS and PTHR1-(AAAG)5 (P = 0.048) and PTHR1-(AAAG)6 (P = 0.023), as well as between PTHR1-(AAAG)5 and height (P = 0.048), but we did not detect any significant within-family association or total-family association between the VDR, COL1A1, PTH, and PTHR1 gene polymorphisms and the variations in BS and height in our sample. Our results do not support that the VDR, COL1A1, PTH, and PTHR1 genes have an important influence on the variation in BS and height in our Chinese population.

Absorptiometry, Photon↗
PubMed2005

A perspective on how the Vitamin D sterol/Vitamin D receptor (VDR) conformational ensemble model can potentially be used to understand the structure-function results of A-ring modified Vitamin D sterols.

The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) (1,25D) activates both genomic and non-genomic intracellular signaling cascades. It is also well recognized that co-incubation of 1,25D with its C-1 epimer, 1beta,25D (HL), suppresses the efficiency of the non-genomic signal activated by 1,25D alone and that its C-3 epimer, 3alpha-1,25D (HJ) is nearly as potent as 1,25D in suppressing PTH secretion, believed to be propagated by 1,25D's genomic signaling. Both these sterols lack the hypercalcemic effect induced by pharmacological doses of 1,25D and have reduced VDR affinity compared to 1,25D, as measured in a steroid competition assay. Recent functional studies suggest that the VDR is required for both non-genomic and genomic signaling. Along these lines we have recently proposed a Vitamin D sterol/VDR conformational ensemble model that posits the VDR contains two distinct, yet overlapping ligand binding sites, and that the potential differential stabilities of 1,25D and HL in these two pockets can be used to explain their different non-genomic signaling properties. The overlapping region is predominantly occupied by the sterol's A-ring when it is bound to either the genomic ligand binding pocket (G-pocket), defined by X-ray crystallography, or the alternative ligand binding pocket (A-pocket), discovered using in silico techniques (directed docking). Therefore, to gain further insight into the potential application of this model we docked the other A-ring diastereomer [(1beta,3alpha)=HH] of 1,25D and its 1- and 3-deoxy forms (25D and CF, respectively) to the A- and G-pockets to assess their potential stabilities in the pockets, relative to 1,25D. The models were then used to provide putative mechanistic arguments for their known structure-function experimental results. This model may provide new insights into how Vitamin D sterols that uncouple the unwanted hypercalcemic effect from attractive growth inhibitory/differentiation properties can do so by differentially stabilizing different subpopulations of VDR conformational ensemble members.

Animals↗
PubMed2005

Applications of the Vitamin D sterol-Vitamin D receptor (VDR) conformational ensemble model.

Over the past 20 years much has been learned about the cellular actions of the steroid hormone 1alpha,25(OH)2-Vitamin D3 (1,25D). Perhaps most importantly structure-function studies led to the discovery that different chemical and physical features of 1,25D are preferred to initiate either exonuclear, non-genomic or endonuclear, genomic cellular signaling. It is well documented that both a 1alpha-OH and 25-OH, and a 6-s-trans, bowl-shaped, sterol conformation are absolutely required for efficient gene transcription, while 6-s-cis locked analogs and 1-deoxy, 25(OH)D3 metabolites activate a variety of non-genomic, rapid responses. These results and the observation that S237 (helix-3; H3) and R274 (H5) are the most static residues in the human 1,25D-Vitamin D receptor (VDR) X-ray construct (see B-values in pdb: 1DB1) and form H-bonds with the 1alpha-OH of 1,25D in the X-ray, genomic pocket (G-pocket), provided the basis for the molecular modeling experiments that led to the discovery of a putative VDR alternative ligand binding pocket (A-pocket). The conformational ensemble model generated from the in silico results provides an explanation for how the VDR can function as a receptor propagating both genomic and non-genomic signaling events. In this report the theoretical gating properties controlling ligand access to the A- and G-pockets will be compared and the model will be used to provide a molecular explanation for the confusing structure-function results pertaining to 1,25D, its side-chain metabolite, 23S,25R-1alpha,25(OH)2-D3-26,23-lactone (BS), and its synthetic two side-chain analog, 21-(3'-hydroxy-3'-methylbutyl)-1alpha,25(OH)2-D3 (KH or Gemini). In addition, evidence that the model is consistent with the pH requirement for Vitamin D sterol-VDR crystallization will be presented.

Arginine↗
PubMed2001

Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers.

Oestrogen/oestrogen receptor (ER) and vitamin D/vitamin D receptor (VDR) systems have been implicated in the pathogenesis of colorectal cancers. The expression of erbB-2 and epidermal growth factor receptor (EGFR) in colorectal cancers has been suggested to have diagnostic and prognostic significance. In our study, XbaI and PvuII polymorphisms of the ER gene and the BsmI polymorphism of the VDR gene were studied in 56 Caucasian patients with rectal cancer. The relationship between the ER and VDR genotypes and the expression of oncogenes was also investigated. The presence of the x allele of ER gene significantly correlated with the overexpression of the erbB-2 and EGFR oncogenes. Significantly increased erbB-2 expression was observed in patients with the VDR B allele. The XXbb allelic combination of the ER/VDR genes was associated with a significantly lower erbB-2 expression, whereas in the other genotypes significantly higher oncogene expression was seen. Our data raise the possibility that ER/VDR gene polymorphisms accompanied by variable oncogene expression might influence the pathogenetic processes of colorectal cancers.

Adult↗
PubMed1999

Novel nonsecosteroidal vitamin D mimics exert VDR-modulating activities with less calcium mobilization than 1,25-dihydroxyvitamin D3.

BACKGROUND: The secosteroid 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) acts through the vitamin D receptor (VDR) to elicit many activities that make it a promising drug candidate for the treatment of a number of diseases, including cancer and psoriasis. Clinical use of 1,25(OH)2D3 has been limited by hypercalcemia elicited by pharmacologically effective doses. We hypothesized that structurally distinct, nonsecosteroidal mimics of 1,25(OH)2D3 might have different activity profiles from vitamin D analogs, and set out to discover such compounds by screening small-molecule libraries. RESULTS: A bis-phenyl derivative was found to activate VDR in a transactivation screening assay. Additional related compounds were synthesized that mimicked various activities of 1,25(OH)2D3, including growth inhibition of cancer cells and keratinocytes, as well as induction of leukemic cell differentiation. In contrast to 1, 25(OH)2D3, these synthetic compounds did not demonstrate appreciable binding to serum vitamin D binding protein, a property that is correlated with fewer calcium effects in vivo. Two mimics tested in mice showed greater induction of a VDR target gene with less elevation of serum calcium than 1,25(OH)2D3. CONCLUSIONS: These novel VDR modulators may have potential as therapeutics for cancer, leukemia and psoriasis with less calcium mobilization side effects than are associated with secosteroidal 1,25(OH)2D3 analogs.

Animals↗
PubMed1995

Transcriptional activity of a fluorinated vitamin D analog on VDR-RXR-mediated gene expression.

The transcriptional activity of the hexafluorinated derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 [F6-1,25-(OH)2D3], was examined in cultured cells by a transient expression assay (CAT assay) using expression vectors for the rat nuclear vitamin D3 receptor (VDR) and the rat 9-cis-retinoic acid receptor (RXR beta), and a reporter plasmid containing a consensus vitamin D3 response element (VDRE) consisting of two directly repeated AGGTCA motifs spaced by 3 bp (DR3). At physiological concentrations, the transcriptional activity of F6-1,25-(OH)2D3 was 2-4 times more potent than that of 1,25-(OH)2D3 in both nontarget (HeLa) and target (UMR106) cells for 1,25-(OH)2D3. The transcriptional activity of F6-1,25-(OH)2D3 was also higher when the endogenous target gene (osteopontin), which has a VDRE related to the DR3 in its promoter, was induced. A gel-shift assay using DR3 as a probe and in vitro synthesized receptors showed that the ligand-induced DNA binding of VDR required RXR to form a heterodimer. Moreover, in this assay we found that F6-1,25-(OH)2D3 induced the receptor-DNA complex at a 10-fold lower concentration than 1,25-(OH)2D3 without influencing the dissociation kinetics. However, the binding affinity of F6-1,25-(OH)2D3 for VDR was slightly lower than that of 1,25-(OH)2D3. The increased DNA binding of ligand-bound VDR by introducing hexafluorines into 1,25-(OH)2D3 may potentiate the transcriptional activity. Thus, the higher biological activity of F6-1,25-(OH)2D3 may be exerted at least in part by enhanced transcriptional activity.

Animals↗
PubMed2003

CYP3A4 and VDR gene polymorphisms and the risk of prostate cancer in men with benign prostate hyperplasia.

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been associated with PRCa. Many candidate genes have been suggested to be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. The vitamin D receptor (VDR) and CYP3A4 have been shown to be involved in the regulation of cell proliferation and differentiation in prostate cells. Genetic variations of these genes have been associated with PRCa in case-control studies and may be useful to detect BPH patients that have a higher risk of developing PRCa. The association between CYP3A4 and VDR TaqI SNPs and the risk of developing PRCa have been investigated in this study by determining the variant genotype frequencies of both SNPs in 400 patients with BPH who have been followed clinically for a median of 11 years. The results of this study showed that the incidence rate of PRCa was higher in BPH patients having CYP3A4 variant genotype compared to those with wild type (relative risk (RR)=2.7; 95% CI=0.77-7.66). No association between variant genotype and risk of developing PRCa was observed with the VDR TaqI variant genotype. In addition, the results of combined genotype analysis of these two SNPs showed a borderline significant association between CYP3A4 and VDR TaqI combined variant genotypes and PRCa risk (RR=3.43; 95% CI=0.99-11.77). While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease.

Case-Control Studies↗
PubMed2002

Effect of VDR polymorphisms on growth and bone mineral density in homozygous beta thalassaemia.

We examined the effect of vitamin D receptor (VDR) polymorphisms at exon 2 (FokI) and intron 8 (BsmI) on the stature and bone mineral density at femoral neck (FBMD) and lumbar spine (LBMD) in 108 prepubertal and pubertal homozygous beta thalassaemic patients, regularly treated. We found significantly shorter stature and lower LBMD and FBMD in all patients with CC VDR genotype, and significant shorter height and lower LBMD in prepubertal and pubertal female patients with BB VDR genotype. Because homozygous CC and BB VDR genotypes influence Vitamin D activity, they can be considered additional risk factors for bone disease in beta thalassaemia.

Adolescent↗
PubMed2003

Effect of VDR gene polymorphisms on osteocalcin secretion in calcitriol-stimulated human osteoblasts.

BACKGROUND: The impact of vitamin D receptor (VDR) gene polymorphisms in bone metabolism remains controversial. Some authors have found a beneficial effect of some VDR gene polymorphisms, while others found no differences, or even a lower bone mass in subjects with the same type of polymorphisms. The aim of this study was to assess if the VDR gene polymorphisms could have an effect on the calcitriol-stimulated osteocalcin in human osteoblasts. METHODS: Osteoblasts were obtained from human femoral necks replaced because of osteoarthritis. Bones were cut into pieces of 1 to 2 mm and placed in a nylon mesh. After the migration of osteoblasts, the pieces were collected and cultured with different concentrations of calcitriol (10(-8), 10(-9), and 10(-1)0 mol/L). After 48 hours of incubation with calcitriol, the osteocalcin secreted into the medium (corrected by either total proteins or total DNA content) was measured. The DNA was extracted from the osteoblasts, amplified by polymerase chain reaction (PCR), and analyzed for target sequences sites of the BsmI, ApaI, TaqI, and FokI restriction enzymes. RESULTS: The response observed in osteocalcin secretion in the bb or TT genotypes doubled the response observed in the BB or tt genotypes (calcitriol 10(-8) and 10(-9) mol/L). A slight trend was also observed with the aa genotype. Men showed higher levels of osteocalcin secretion than women. Age did not show any influence in osteocalcin secretion. CONCLUSION: VDR alleles and gender demonstrated an effect on the osteocalcin secretion. BB or tt genotypes, and also the "A" allele, showed the lowest calcitriol-stimulated osteocalcin secretion.

Aged↗
PubMed1994

Difference and similarity of DNA sequence recognized by VDR homodimer and VDR/RXR heterodimer.

Nuclear receptors for the thyroid hormone and vitamin A and D cooperate with the retinoid X receptor (RXR) in activating the transcription. Although the hormone response elements for these receptors have been proposed in which spacing of the direct repeated motifs determine the specificity (so called 3-4-5 rule), vitamin D response elements (VDREs) in the natural context consist of often imperfect direct repeats. Vitamin D receptor (VDR) alone can bind to the mouse osteopontin (mSPP-1) VDRE, which contains a direct repeat separated by 3 nucleotides, but not to the rat osteocalcin (rOST) VDRE having inexact direct repeat. The presence of RXR not only allows the VDR to bind to the rOST VDRE, but also increases the binding affinity for the mSPP-1 VDRE. The RXR/VDR heterodimer exhibits the similar affinity constants for the mSPP-1 VDRE and the rOST VDRE, in spite of the apparently different affinities for two VDREs of the VDR homodimer. A random oligonucleotide selection procedure revealed that the consensus sequence selected by the RXR homodimer is the direct repeat spaced by one A residue. In contrast, the sequences preferentially selected by the VDR homodimer and the VDR/RXR heterodimer are similar, which are the direct repeats spaced by 3 nucleotides. The difference and similarity of DNA sequence recognition are discussed.

Animals↗
PubMed1998

Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking, and aromatic DNA adduct levels in human right atrial tissue.

Cancer and cardiovascular diseases share risk factors such as smoking, and the onset of both diseases have been suggested to have a common mechanistic basis. The binding of carcinogens to DNA (carcinogen-DNA adducts), genetic polymorphisms in carcinogen-detoxifying enzymes glutathione S-transferases (GSTs), and genetic polymorphisms in the vitamin D receptor (VDR) are among the candidates for modifiers of cancer risk. We determined whether these biomarkers could be related to individual characteristics of patients suffering from cardiovascular diseases. For that purpose, DNA from the right atrial appendage of 41 patients who underwent open heart surgery was analyzed for smoking-related DNA adducts and polymorphisms in GSTM1, GSTT1, and VDR genes. Statistical analysis was used to identify any patient's characteristics associated with these molecular markers. Our results showed that heart tissue of cigarette smokers contained a variety of aromatic DNA adducts in significantly elevated levels compared to ex-smokers (P<0.01) or nonsmokers (P<0.001). A linear relationship was observed between DNA adduct levels and daily cigarette smoking (rs=0.73; P=0.0003). Since cardiac myocytes are terminally differentiated cells that have lost their ability to divide and seemingly have limited DNA repair capacities, their levels might accumulate with time and thereby affect heart cell function or viability. Substantial interindividual differences between DNA adduct levels were observed, and persons with severe coronary artery disease (CAD), as assessed by coronary angiography, had higher DNA adduct levels than persons with no or mild CAD (P=0.04). As polymorphisms in GST genes have been shown to modulate DNA adduct levels and risk for lung cancer in smokers, we explored for the first time whether the GST polymorphisms could also explain deviating heart DNA adduct levels and CAD risk. However, no relation could be found between these covariants. In contrast, a VDR genotype, which has been associated with decreased serum levels of the active hormonal form of vitamin D and increased risk for certain cancers, seemed to be related to severity of CAD (P=0.025). Our findings support the hypothesis that smoking-related DNA damage may be involved in the onset of cardiovascular diseases and suggest that VDR genotype may be a useful susceptibility marker of CAD.

Adult↗
PubMed2005

Influence of IL-6, COL1A1, and VDR gene polymorphisms on bone mineral density in Crohn's disease.

BACKGROUND: Osteoporosis is an important cause of morbidity in patients with Crohn's disease. The pathogenesis of reduced bone mineral density (BMD) is multifactorial. A range of genetic factors have been implicated in other populations of patients with osteoporosis. AIM: To investigate the influence of interleukin 6 (IL-6), collagen type 1alpha1 (COL1A1), and vitamin D receptor gene (VDR) single nucleotide polymorphisms (SNP) on BMD in patients with Crohn's disease. PATIENTS: A cohort of 245 well characterised patients with Crohn's disease were recruited from the inflammatory bowel disease register at the Freeman Hospital and Royal Victoria Infirmary, Newcastle upon Tyne, and the Queen Elizabeth Hospital, Gateshead, UK. METHODS: Patients were genotyped for IL-6 C-174G SNP, COL1A1 Sp1 binding site G T SNP, VDR Taq1, and Fok1 SNPs, and CARD15 R702W, G908R, and L1007fs SNPs. BMD was measured at the lumbar spine (LSP) and hip using dual energy x ray absorptiometry. RESULTS: A total of 158 female and 87 male patients, aged 24-70 years (mean 44), were recruited. There were no significant differences in the distribution of the tested SNPs when analysed for age, body mass index, pre/post-menopausal status, smoking, or steroid use. Two hundred and thirteen patients were genotyped for the IL-6 SNP. LSP and total hip BMD was significantly lower in patients with the GG genotype (48%) than the CC genotype (15%) (p = 0.041, p = 0.014). One hundred and eighty patients were genotyped for the COL1A1 SNP. There was no significant difference in BMD at LSP. Hip BMD was significantly lower in heterozygous patients compared with homozygous wild-types (p = 0.034). There were no significant differences in BMD between genotypes for the two VDR SNPs or the CARD15 genotypes examined. CONCLUSION: IL-6 and COL1A1 gene polymorphisms influence BMD in patients with Crohn's disease but the particular VDR gene polymorphisms studied do not have a major effect.

Adrenal Cortex Hormones↗