- About this Journal ·
- Abstracting and Indexing ·
- Aims and Scope ·
- Annual Issues ·
- Article Processing Charges ·
- Articles in Press ·
- Author Guidelines ·
- Bibliographic Information ·
- Citations to this Journal ·
- Contact Information ·
- Editorial Board ·
- Editorial Workflow ·
- Free eTOC Alerts ·
- Publication Ethics ·
- Reviewers Acknowledgment ·
- Submit a Manuscript ·
- Subscription Information ·
- Table of Contents
BioMed Research International
Volume 2014 (2014), Article ID 304250, 8 pages
The Role of Vitamin D Deficiency and Vitamin D Receptor Genotypes on the Degree of Collateralization in Patients with Suspected Coronary Artery Disease
1Department of Medicine, Section of Endocrinology, Nutrition, and Diabetes, Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, MA 02118, USA
2Tehran University of Medical Sciences, Tehran 1417653911, Iran
3Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran 1417653911, Iran
4Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1417653911, Iran
Received 26 April 2013; Revised 20 January 2014; Accepted 25 January 2014; Published 6 March 2014
Academic Editor: M. Ilyas Kamboh
Copyright © 2014 Arash Hossein-Nezhad et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
We determined the association of vitamin D deficiency and the FokI polymorphism of the vitamin D receptor (VDR) gene in 760 patients who underwent angiography due to suspected coronary artery disease (CAD). Angiography and the Rentrop scoring system were used to classify the severity of CAD in each patient and to grade the extent of collateral development, respectively. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the FokI VDR gene polymorphism. The prevalence of severe vitamin D deficiency (serum 25(OH)D < 10 ng/mL) was significantly higher in patients with at least one stenotic coronary artery compared to those without any stenotic coronary arteries. Severe vitamin D deficiency was not independently associated with collateralization, but it was significantly associated with the VDR genotypes. In turn, VDR genotype was independently associated with the degree of collateralization; the Rentrop scores were the highest in FF, intermediate in Ff, and the lowest in the ff genotype. The results show that FokI polymorphism is independently associated with collateralization. Additionally, vitamin D deficiency is more prevalent in patients with CAD that may result from FokI polymorphism. Therefore, maintaining a normal vitamin D status should be a high priority for patients with CAD.
The active form of vitamin D, 1α,25-dihydroxyvitamin D [1α,25(OH)2D], plays an important role in the endocrine system by exerting its influence on various metabolic pathways. It has been documented that vitamin D deficiency is associated with a constellation of chronic disorders such as autoimmune diseases, certain cancers, and osteoporosis . Recent studies have demonstrated that vitamin D deficiency is independently associated with the prevalence of cardiovascular disease . Vitamin D deficiency has also been associated with an increased risk of incident hypertension , diabetes , and hyperlipidemia , which are the known risk factors for the development of cardiovascular disease [4–8]. Numerous experimental and epidemiological studies have demonstrated that the levels of the circulating form of vitamin D, 25-hydroxyvitamin D3 [25(OH)D3], are inversely associated with increased mortality from cardiovascular and heart diseases [9–11]. Vitamin D supplementation has been shown to have some protective value in the primary prevention of coronary heart disease . Most importantly, a growing body of evidence indicates that maintaining the serum 25(OH)D3 levels within the normal range may be beneficial for general health , suggesting that measuring serum levels of 25(OH)D3 may be clinically valuable to predict patients’ susceptibility to coronary artery disease [13, 14]. There are compelling lines of evidence which confirmed that 25(OH)D3 levels play a major role in the health of a wide variety of organ systems . An inverse association between vitamin D deficiency and the prevalence of cardiometabolic risk factors, such as type 2 diabetes, hypertension, dyslipidaemia, and the metabolic syndrome has been reported . Moreover, the concentration of 25(OH)D3 is considered as a clinical valuable marker to predict the risk of CAD. Vitamin D deficiency has been associated with an increased risk of CAD and cardiovascular death. Endothelial dysfunction plays an important role in pathogenesis of CAD and vitamin D deficiency is postulated to promote endothelial dysfunction. According to previous studies, patients with vitamin D deficiency had also significantly higher prevalence of double- or triple-vessel CAD, diffuse CAD, and higher number of coronary vessels involved as compared to those with higher 25(OH)D3 levels .
The biological actions of vitamin D are mediated through the nuclear vitamin D receptor (VDR) . VDR forms a heterodimer with the retinoid X receptor (RXR) while 1α,25(OH)2D acts as a ligand forming a 1α,25(OH)2D/VDR complex. This ligand-bound VDR complex then binds to a sequence or sequences, called VDR response elements (VDREs), in the promoter region of target genes and acts as a transcription factor to promote gene expression. The precise mechanism of how the ligand/VDR complex may help protect individuals against cardiovascular diseases is not clear. It has been documented that vitamin D has functional roles in cellular proliferation, including different stages of the cell cycle, differentiation, and apoptosis [17, 18] that could have impact on normal angiogenesis and endothelial cell differentiation . VDR is expressed in almost all tissues and in a wide variety of cell types, including cardiomyocytes, vascular smooth muscle cells, and endothelial cells [20, 21]. In addition, macrophages, monocytes, endothelial cells, and vascular smooth muscle cells have the capability to activate vitamin D locally in an autocrine fashion . The presence of VDR in vascular smooth muscle cells and endothelial cells coupled with the ability of vascular tissues to activate vitamin D locally suggests a role vitamin D may play in normal vascular physiology and its role in the prevention of ischemic heart disease.
Coronary collateral arteries are believed to improve the prognosis of patients with ischemic heart diseases like CAD by preserving perfusion and function of the myocardium . In this study, our aims are to determine whether vitamin D deficiency is associated with collateralization and whether the FokI polymorphism of the VDR gene could affect collateralization in CAD patients. Understanding the underlying molecular genetics involved in the collateral development may be clinically valuable to formulate prevention strategies for patients who are at an increased risk for CAD.
Likewise, in order to better understand the role of the ligand-bound VDR in the degree of collateralization the role of specific elements of the VDR gene in modifying VDR function should be considered. Previously, we have provided evidence indicating that different VDR genotypes may be associated with different functions of vitamin D [23, 24]. Among the multiple polymorphisms of the VDR gene, FokI polymorphism (rs10735810) is the only one without any link to other VDR polymorphisms and is the sole polymorphism that leads to two different VDR protein products [25, 26]. In the presence of a FokI polymorphism, an alternative in-frame start codon, located 10 nucleotides downstream, initiates transcription. The FokI polymorphism causes transcription to begin at the second ATG start codon in the exon 2 and ultimately results in the translation of a potentially shortened receptor protein. The F allele codes 3 amino acid shorter VDR sequence than that coded by the f allele. Some studies have argued that the VDR coded by the F allele is more efficient in transactivating target genes [27–29]. According to recent clinical and experimental studies, VDR may indeed play a role in cardiovascular diseases and the VDR gene polymorphism could have an important role in transactivation efficiency of target genes [17, 18].
2. Materials and Methods
2.1. Patient Selection
The current cross-sectional study included 760 individuals who underwent a clinical assessment and a treatment program between October 2007 and March 2011 at cardiology clinics of major hospitals affiliated to Tehran University of Medical Sciences. Exclusion criteria were endocrine disorders, inflammatory diseases, history of previous heart attack, previous cardiac surgery, malignancies, and known chronic diseases with the exception of classic risk factors of CAD. The ethics committee of Endocrinology and Metabolism Research Institute approved the study protocol. At the time of recruitment, all participants provided written informed consent to participate in all stages of the study, including DNA genotyping.
2.2. Physical Examination
Clinical information was obtained using a standardized health questionnaire, and a general practitioner performed the physical examination. Body mass index (BMI) was calculated as body weight divided by the square of height expressed in kg/m2. Blood pressure was measured two times using a standard calibrated mercury sphygmomanometer on the right arm of participants after they remained seated for 15 minutes. The mean of two blood pressure measurements was recorded as blood pressure. Left ventricular ejection fraction was measured using echocardiography. Angiography was performed on patients who presented with cardiac chest pain and a positive exercise test.
2.3. Coronary Angiography and CAD Classification
A cardiology specialist performed the angiogram on each of the patients for whom angiography was indicated. Following angiography, patients were grouped to four classes based on luminal stenosis and the number of coronary arteries involved. In class 0, luminal stenosis was less than 50% and considered normal. In all other classes, where luminal stenosis was more than 50%, the participants were considered CAD patients: In class 1, luminal stenosis was more than 50% in one artery; in class 2, luminal stenosis was more than 50% in two arteries; in class 3, luminal stenosis was more than 50% in three arteries. According to this classification 84.5% of participants were considered CAD patients (classes 1–3).
2.4. Coronary Angiography and Collateral Grading/Group
The Rentrop scoring system  was used to grade the extent of the degree of collateralization in study subjects: in grade 0, no filling was visible in any collateral channels; in grade 1, collateral filling was visible in side branches of the vessel without dye reaching the epicardial segment of that vessel; in grade 2, partial collateral filling was visible in the epicardial segment of the vessel; in grade 3, complete collateral filling was visible in the vessel. When multiple coronary arteries were involved, the highest Rentrop score was considered as the patient’s extent of the degree of collateralization. Based on Rentrop scores, patients were categorized into either a poor-collateralization group (grades 0-1) or a well-collateralization group (grades 2-3).
2.5. Blood Sampling
Patients fasted for 12 hours before 12 mL of peripheral venous blood was collected from the patients. Blood samples were added to two aliquots tubes (each 4 mL) for serum preparation and the other 4 mL was added to EDTA tube for DNA isolation. All separated sera and EDTA tubes were stored at −80°C.
2.6. Biochemical and Genetic Analyses
Various biochemical analyses were performed in serum obtained from peripheral venous blood after centrifugation at 2,000 ×g for 20 minutes in a refrigerated centrifuge. Serum 25(OH)D was measured by radioimmunoassay (RIA) using a Biosource kit (Biosource Europe SA, Belgium); intra- and interassay coefficients of variation (CV) were 5.2% and 7.5%, respectively. Fasting blood sugar (FBS), triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were measured using a Randox laboratories kit (Hitachi 902). Fasting blood sugar was measured by the GOD/PAP method. Triglyceride was measured by the GPO-PAP method. Total cholesterol was measured by Enzymatic Endpoint. Direct high- and low-density lipoprotein was measured by enzymatic clearance assay. Cardiovascular risk was determined in accordance with the World Health Organization’s criteria for cardiovascular risk factors : TC > 200 mg/dL, LDL > 160 mg/dL, TG > 150 mg/dL, FBS > 110, HDL < 35 mg/dL, and hypertensive BP ≥ 140/90 mmHg or patients with their blood pressure controlled by antihypertensive medication.
Genomic DNA extraction was performed using a FlexiGen DNA kit (QIAGEN kit), according to the manufacturer’s protocol. The FokI polymorphism in exon 2 of the VDR gene was detected by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). PCR-RFLP was confirmed by repeated analysis, and genotyping was confirmed by sequencing 15% of total PCR products.
2.7. Statistical Analysis
Data were analyzed using SPSS software, version 11.5. Student’s -test and analysis of variance (ANOVA) compared differences between the means of continuous variables. The chi-square test compared differences between categorical variables. We used univariate analysis from General Linear Model (GLM). In this model, we controlled the effect of confounding variable including age, sex, severity of CAD, and cardiovascular risk factors (higher TG, higher FBS, higher total cholesterol, higher BMI, and lower ejection fraction) on dependent variable through inserting them as covariates. In all tests, the level of significance was set at 0.05 ().
This study included 582 men and 178 women with a total of 760 subjects who underwent angiography. The mean age was 57.97 ± 10.58 years. The clinical and biochemical risk factors of participants are shown in Table 1. The mean serum 25(OH)D level of the participants was 7.2 ± 5.2 ng/mL. Ninety-eight% of the participants had serum 25(OH)D levels less than 20 ng/mL and were considered as vitamin D deficient . Among the vitamin D deficient participants, 70% had serum 25(OH)D levels less than 10 ng/mL and were considered severe vitamin D deficient (62% of women, 72% of men).
(A) CAD Classification, Cardiovascular Risk Factors, and Vitamin D Deficiency. Patients with class 3 CAD were older () with higher TG () and lower HDL () compared to other classes. There were no significant associations between CAD classes and hypertension, LDL, TC, or impaired FBS (blood sugar > 110 mg/dL) (Table 1).
Severe vitamin D deficiency (<10 ng/mL) was significantly more frequent in subject with classes 1–3 (CAD patients) than in class 0 (75% versus 56.8%, ). Class 3 CAD patients had a significantly higher prevalence of severe vitamin D deficiency compared to other classes () (Table 1).
There were significant associations between severe vitamin D deficiency and hypertension ( values = 0.007), impaired FBS ( values = 0.007), higher TG ( values = 0.002), lower HDL ( values = 0.001), and higher TC ( values = 0.02).
(B) CAD Classification, Cardiovascular Risk Factors, and VDR Genotypes. Demographics regarding genotype are summarized in Table 2. 54.5% of participants were homozygous for the F allele, 7.6% were homozygous for the f allele, and 37.89% were heterozygous. No significant differences in VDR genotypes or allele frequencies were observed between different classes of CAD. Interestingly, patients with ff genotype were significantly younger than those with other genotypes ( value = 0.003).
Significant differences in some cardiovascular risk factors were found, including higher TG (), higher FBS (), higher total cholesterol (), and higher BMI () as well as lower ejection fraction () among participants with different genotypes, but there were no significant differences in other risk factors, including smoking (), hypertension (), lower HDL (), or higher LDL ().
The prevalence of severe vitamin D deficiency was significantly higher in patients with ff and Ff genotypes compared to patients with FF genotype ().
(C) CAD Class, Vitamin D Status, VDR Genotype, and the Degree of Collateralization. The relationship between VDR genotype with CAD classification, vitamin status, and degree of collateralization was summarized in Table 3. There was a significant and linear association between the degree of collateralization and CAD class. The percent of CAD patients in the well-collateralization group increased with CAD class; 50.5% for class 1, 74.8% for class 2, and 92% for class 3.
Our results demonstrate that patients in the poor-collateralization group had a higher prevalence of severe vitamin D deficiency than the well-collateralization group (poor-collateral group; 75.2% versus well-collateral group; 66.5%, ).
VDR genotype was significantly associated with collateral development. 80.2% of patients with the FF genotype were in the well-collateralization group compared to only 51.72% of those with the ff genotype who were in the well-collateralization group (). Following logistical regression analysis, we found that carriers of the f allele (patients with ff and Ff genotypes) were associated with the poor-collateral group (). After adjustment for age, sex, severity of CAD, and cardiovascular risk factors (higher TG, higher FBS, higher total cholesterol, higher BMI, and lower ejection fraction), FF genotype was still significantly associated with the well-collateral group (). The relative risk of having poor-collateralization group was 1.5 for patients with ff genotypes (OR: 1.96, 95% CI: 1.14 to 3.37, ).
The first aim of this study was to determine whether vitamin D deficiency could be associated with the degree of collateralization. Our results showed that vitamin D deficiency was more prevalent in patients with CAD. Ninety-eight% of patients had serum 25(OH)D levels less than 20 ng/mL, and 69.73% of patients had serum vitamin D levels less than 10 ng/mL that is considered as vitamin D deficient and severe vitamin D deficient, respectively. Serum 25(OH)D levels have been shown to be inversely associated with severity of CAD. A growing body of evidence reveals that vitamin D deficiency is more prevalent in patients with ischemic heart disease, suggesting that vitamin D deficient patients may be also more susceptible to cardiovascular diseases [2, 32, 33]. Our findings support the plethora of existing evidence that suggests vitamin D deficiency has a predictive role in the development of CAD [2, 33, 34].
Our data showed that vitamin D deficiency was more common among patients in the poor-collateralization group compared to patients in the well-collateralization group. According to experimental data, vascular tissue expresses VDR and is potentially an important target for vitamin D; therefore, it has been suggested that vitamin D may have a protective role in the vascular system . The precise mechanisms of how vitamin D protects against CAD have not been fully delineated. However, we do know that both vascular cells and immune cells can locally synthesize 1α,25(OH)2D and that VDR is expressed in both cell types. Taken together, this evidence suggests a biological role for vitamin D in cardiovascular function and angiogenesis [36, 37], such as enhancing collateral development. Thus, the role the vitamin D may play in collateralization is explained by several biologically indirect mechanisms, namely, some of the known cardiovascular risk factors. Our results showed that there was indeed an association between severe vitamin D deficiency and these same three risk factors; hypertension, higher FBS, and higher total cholesterol levels along with two additional risk factors; higher TG and lower HDL.
Recent evidence showed that certain cardiovascular risk factors such as hypertension, hyperglycemia, and hypercholesterolemia could affect the vascular growth processes and impair the normal capacity for vascular growth [38, 39]. Numerous epidemiological studies have also demonstrated that vitamin D deficiency is correlated with the aforementioned risk factors by different mechanisms [40–42].
In one such study regarding the risk factor hypertension, vitamin D has been shown to directly control blood pressure as a negative regulator of rennin-angiotensin system . Regarding hyperglycemia, vitamin D deficiency has been correlated with beta-cell dysfunction and insulin resistance . A meta-analysis of several clinical studies has also shown that lower levels of vitamin D and calcium may impair glucose metabolism and suggested that a combined supplementation of vitamin D with calcium could have a beneficial effect on controlling glucose homeostasis . Prior studies have also demonstrated that low serum levels of vitamin D were associated with obesity, hypertriglyceridemia, and lower HDL levels [44, 45] by some ill-defined mechanisms. Hence, based on the fact that vitamin D deficiency has been associated with certain cardiovascular risk factors, it is likely that vitamin D deficiency could interfere with collateral artery development by altering the complicated process of pathological changes that may be influenced by these very same cardiovascular risk factors.
The second aim of this study was to examine potential relationships between VDR genotype and collateralization in CAD patients. To investigate if the VDR gene plays a role in collateralization, we first investigated relationships between FokI polymorphism and severities of CAD, which has a direct effect on collateral development by itself. No significant difference between VDR genotype and severity of CAD was found. Consistent with our result, Pan et al. found no association between FokI polymorphism and CAD . Several studies have demonstrated that a wide variety of cells express VDR, suggesting that vitamin D may be involved in regulating different cellular processes, including proliferation, differentiation, and migration [10, 18, 47] that are involved in the progression of CAD . Thus, it is likely the FokI polymorphism has a functional role in CAD indirectly via vitamin D deficiency. In addition, our results demonstrated that vitamin D deficiency was more common in patients with Ff and ff genotypes and less common in patients with FF genotype.
The extent of collateralization was the highest in FF, intermediate in Ff genotype, and the lowest in ff, suggesting that FokI may be functional polymorphism of VDR in collateralization. Few studies have looked at what effects the FokI polymorphism has on VDR function. A transcription activation study performed by Arai et al. studied the activity of two proteins in transfected HeLa cells including a vitamin D response element (VDRE). Their results showed that the shorter VDR protein was the more active form compared to the long variant; an increase of approximately 1.7-fold . Using a reporter gene assay, Jurutka et al. also demonstrated that a natural polymorphic variant of human VDR, resulting from missing a FokI restriction site, which lacks the first three amino acids, interacted more efficiently with the human basal transcription factor IIB (TFIIB). They further suggested that the F-variant is more effective than f-variant as a transcription factor .
The cross-sectional design of our study limited our ability to determine the role FokI polymorphism may play in vascular collateralization. Despite the limitation of our study, angiographic and laboratory data are unique to our study allowing us to control most confounders. Another strength of our study is the homogeneity of population that allowed us to effectively evaluate vitamin D and the VDR gene variant in relation to cardiovascular risk factors, severity of CAD, and collateralization.
From our study we suggest that FokI polymorphism may predispose patients to CAD via vitamin D deficiency. Maintaining a normal vitamin D status should be a high priority in general population. Likewise, vitamin D supplementation may be beneficial in the prevention of CAD in patients with an increased risk for CAD. The FokI VDR polymorphism may have an independent association with collateralization, suggesting that genetic predisposition may contribute to different degrees of collateralization, independent of vitamin D deficiency.
Identification of the genetic basis and the pathways involved in CAD can herald a new era in diagnosis, treatment, and prevention of this disease. It is well established that functional coronary collateral arteries are of paramount importance in the prognosis of CAD. Our study may unveil a new aspect of the FokI polymorphism and the role of the VDR/vitamin D complex in collateral development.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors are grateful to all participants in the study for their dedication and contribution to the research.
- M. F. Holick, “Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers,” Southern Medical Journal, vol. 98, no. 10, pp. 1024–1027, 2005.
- J. Kendrick, G. Targher, G. Smits, and M. Chonchol, “25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey,” Atherosclerosis, vol. 205, no. 1, pp. 255–260, 2009.
- A. Hossein-Nezhad, A. Spira, and M. F. Holick, “Influence of vitamin d status and vitamin d3 supplementation on genome wide expression of white blood cells: a randomized double-blind clinical trial,” PLoS ONE, vol. 8, article 20, 2013.
- J. L. Anderson, H. T. May, B. D. Horne et al., “Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population,” The American Journal of Cardiology, vol. 106, no. 7, pp. 963–968, 2010.
- T. Skaaby, L. L. Husemoen, C. Pisinger, et al., “Vitamin D status and changes in cardiovascular risk factors: a prospective study of a general population,” Cardiology, vol. 123, pp. 62–70, 2012.
- L. T. Wasson, D. Shimbo, M. R. Rubin, J. A. Shaffer, J. E. Schwartz, and K. W. Davidson, “Is vitamin D deficiency a risk factor for ischemic heart disease in patients with established cardiovascular disease? 10-year follow-up of the Nova Scotia Health Survey,” International Journal of Cardiology, vol. 148, no. 3, pp. 387–389, 2011.
- E. D. Michos and M. L. Melamed, “Vitamin D and cardiovascular disease risk,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 11, no. 1, pp. 7–12, 2008.
- S. E. Judd and V. Tangpricha, “Vitamin D deficiency and risk for cardiovascular disease,” The American Journal of the Medical Sciences, vol. 338, no. 1, pp. 40–44, 2009.
- J. H. Lee, J. H. O'Keefe, D. Bell, D. D. Hensrud, and M. F. Holick, “Vitamin D deficiency. An important, common, and easily treatable cardiovascular risk factor?” Journal of the American College of Cardiology, vol. 52, no. 24, pp. 1949–1956, 2008.
- H. Dobnig, S. Pilz, H. Scharnagl et al., “Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality,” Archives of Internal Medicine, vol. 168, no. 12, pp. 1340–1349, 2008.
- S. E. Judd and V. Tangpricha, “Vitamin D therapy and cardiovascular health,” Current Hypertension Reports, vol. 13, no. 3, pp. 187–191, 2011.
- S. N. Bhupathiraju and K. L. Tucker, “Coronary heart disease prevention: nutrients, foods, and dietary patterns,” Clinica Chimica Acta, vol. 412, no. 17-18, pp. 1493–1514, 2011.
- S. K. Syal, A. Kapoor, E. Bhatia, et al., “Vitamin D deficiency, coronary artery disease, and endothelial dysfunction: observations from a coronary angiographic study in Indian patients,” Journal of Invasive Cardiology, vol. 24, pp. 385–389, 2012.
- P. Anagnostis, V. G. Athyros, F. Adamidou, M. Florentin, and A. Karagiannis, “Vitamin D and cardiovascular disease: a novel agent for reducing cardiovascular risk?” Current Vascular Pharmacology, vol. 8, no. 5, pp. 720–730, 2010.
- H. Taskapan, M. Wei, and D. G. Oreopoulos, “25(OH) vitamin D3 in patients with chronic kidney disease and those on dialysis: rediscovering its importance,” International Urology and Nephrology, vol. 38, no. 2, pp. 323–329, 2006.
- P. Lips, “Vitamin D physiology,” Progress in Biophysics and Molecular Biology, vol. 92, pp. 4–8, 2006.
- B. Klotz, B. Mentrup, M. Regensburger et al., “1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity,” PLoS ONE, vol. 7, no. 1, Article ID e29959, 2012.
- J. N. Artaza, F. Sirad, M. G. Ferrini, and K. C. Norris, “1,25(OH)2vitamin D3 inhibits cell proliferation by promoting cell cycle arrest without inducing apoptosis and modifies cell morphology of mesenchymal multipotent cells,” Journal of Steroid Biochemistry and Molecular Biology, vol. 119, no. 1-2, pp. 73–83, 2010.
- P. Furigay and N. Swamy, “Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of calcitriol,” Journal of Steroid Biochemistry and Molecular Biology, vol. 89-90, pp. 427–431, 2004.
- K. A. Nibbelink, D. X. Tishkoff, S. D. Hershey, A. Rahman, and R. U. Simpson, “1,25(OH)2-vitamin D3 actions on cell proliferation, size, gene expression, and receptor localization, in the HL-1 cardiac myocyte,” Journal of Steroid Biochemistry and Molecular Biology, vol. 103, no. 3–5, pp. 533–537, 2007.
- O. Tarcin, D. G. Yavuz, B. Ozben et al., “Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 10, pp. 4023–4030, 2009.
- D. E. Prosser and G. Jones, “Enzymes involved in the activation and inactivation of vitamin D,” Trends in Biochemical Sciences, vol. 29, no. 12, pp. 664–673, 2004.
- R. Bouillon, G. Carmeliet, L. Verlinden et al., “Vitamin D and human health: lessons from vitamin D receptor null mice,” Endocrine Reviews, vol. 29, no. 6, pp. 726–776, 2008.
- A. Hossein-Nezhad, G. Ahangari, H. Behzadi, Z. Maghbooli, and B. Larijani, “Vitamin D receptor gene polymorphism may predict response to vitamin D intake and bone turnover,” Daru, vol. 17, no. 1, pp. 13–19, 2009.
- A. Hossein-Nezhad, G. Ahangari, and B. Larijani, “Evaluating of VDR gene variation and its interaction with immune regulatory molecules in osteoporosis,” Iranian Journal of Public Health, vol. 38, no. 2, pp. 27–36, 2009.
- G. Kerr Whitfield, L. S. Remus, P. W. Jurutka et al., “Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene,” Molecular and Cellular Endocrinology, vol. 177, no. 1-2, pp. 145–159, 2001.
- A. Hossein-nezhad, K. Mirzaei, P. Shabani et al., “Association of VDR gene polymorphism with insulin resistance in diabetic patient's running title: VDR and insulin resistance,” Iranian Journal of Diabetes and Lipid Disorders, vol. 8, no. 1, pp. 143–150, 2009.
- K. Mirzaei, S. Ahmadi, A. Hossein-Nezhad, and F. Mokhtari, “Potential role of OPG/RANKL system and FokI genotypes in pathogenesis and clinical manifestations in multiple sclerosis,” Minerva Medica, vol. 103, pp. 313–321, 2012.
- A. Hossein-Nezhad, F. N. Varzaneh, and K. Mirzaei, “Association of the FokI polymorphism in the vitamin D receptor gene with vertebral fracture in Iranian postmenopapausal women,” Endocrine Practice, vol. 17, no. 5, pp. 826–827, 2011.
- K. P. Rentrop, M. Cohen, H. Blanke, and R. A. Phillips, “Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects,” Journal of the American College of Cardiology, vol. 5, no. 3, pp. 587–592, 1985.
- R. P. Heaney and M. F. Holick, “Why the IOM recommendations for vitamin D are deficient,” Journal of Bone and Mineral Research, vol. 26, no. 3, pp. 455–457, 2011.
- L. T. Wasson, D. Shimbo, M. R. Rubin, J. A. Shaffer, J. E. Schwartz, and K. W. Davidson, “Is vitamin D deficiency a risk factor for ischemic heart disease in patients with established cardiovascular disease? 10-year follow-up of the Nova Scotia Health Survey,” International Journal of Cardiology, vol. 148, no. 3, pp. 387–389, 2011.
- A. Hossein-nezhad and M. F. Holick, “Vitamin D for health: a global perspective,” Mayo Clinic Proceeding, vol. 88, no. 7, pp. 720–755, 2013.
- M. F. Holick, “Vitamin D and sunlight: strategies for cancer prevention and other health benefits,” Clinical Journal of the American Society of Nephrology, vol. 3, no. 5, pp. 1548–1554, 2008.
- A. Zittermann and R. Koerfer, “Vitamin D in the prevention and treatment of coronary heart disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 11, no. 6, pp. 752–757, 2008.
- A. S. Dusso, A. J. Brown, and E. Slatopolsky, “Vitamin D,” The American Journal of Physiology—Renal Physiology, vol. 289, no. 1, pp. F8–F28, 2005.
- I. Chung, G. Han, M. Seshadri et al., “Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo,” Cancer Research, vol. 69, no. 3, pp. 967–975, 2009.
- T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein, “Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions,” Cardiovascular Research, vol. 78, no. 2, pp. 257–264, 2008.
- G. Spinetti, N. Kraenkel, C. Emanueli, and P. Madeddu, “Diabetes and vessel wall remodelling: from mechanistic insights to regenerative therapies,” Cardiovascular Research, vol. 78, no. 2, pp. 265–273, 2008.
- D. De Groot, G. Pasterkamp, and I. E. Hoefer, “Cardiovascular risk factors and collateral artery formation,” European Journal of Clinical Investigation, vol. 39, no. 12, pp. 1036–1047, 2009.
- A. G. Pittas, J. Lau, F. B. Hu, and B. Dawson-Hughes, “Review: the role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2017–2029, 2007.
- C. Zhou, F. Lu, K. Cao, D. Xu, D. Goltzman, and D. Miao, “Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1α-hydroxylase knockout mice,” Kidney International, vol. 74, no. 2, pp. 170–179, 2008.
- E. Hyppönen and C. Power, “Vitamin D status and glucose homeostasis in the 1958 British birth cohort the role of obesity,” Diabetes Care, vol. 29, no. 10, pp. 2244–2246, 2006.
- A. G. Need, P. D. O'Loughlin, M. Horowitz, and B. E. C. Nordin, “Relationship between fasting serum glucose, age, body mass index and serum 25 hydroxyvitamin D in postmenopausal women,” Clinical Endocrinology, vol. 62, no. 6, pp. 738–741, 2005.
- E. S. Ford, U. A. Ajani, L. C. McGuire, and S. Liu, “Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults,” Diabetes Care, vol. 28, no. 5, pp. 1228–1230, 2005.
- X. M. Pan, D. R. Li, L. Yang et al., “No association between vitamin D receptor polymorphisms and coronary artery disease in a Chinese population,” DNA Cell Biology, vol. 28, no. 10, pp. 521–525, 2009.
- M. C. Rebsamen, J. Sun, A. W. Norman, and J. K. Liao, “1α,25-dihydroxyvitamin D3 induces vascular smooth muscle cell migration via activation of phosphatidylinositol 3-kinase,” Circulation Research, vol. 91, no. 1, pp. 17–24, 2002.
- H. Arai, K.-I. Miyamoto, Y. Taketani et al., “A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women,” Journal of Bone and Mineral Research, vol. 12, no. 6, pp. 915–921, 1997.
- P. W. Jurutka, L. S. Remus, G. K. Whitfield et al., “The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB,” Molecular Endocrinology, vol. 14, no. 3, pp. 401–420, 2000.