help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-2407
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taverna, M. J.
Right arrow Articles by Slama, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taverna, M. J.
Right arrow Articles by Slama, G.
Related Collections
Right arrow Calcium and Bone Metabolism
Right arrow Diabetes and Insulin
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4803-4808
Copyright © 2005 by The Endocrine Society

Association between a Protein Polymorphism in the Start Codon of the Vitamin D Receptor Gene and Severe Diabetic Retinopathy in C-Peptide-Negative Type 1 Diabetes

Mariano J. Taverna, Jean-Louis Selam and Gérard Slama

Institut National de la Santé et de la Recherche Médicale U.341, Department of Diabetology, Hôtel-Dieu Hospital, 75181 Paris Cedex 04, Paris, France

Address all correspondence and requests for reprints to: Mariano J. Taverna, M.D., PhD., Institut National de la Santé et de la Recherche Médicale U. 341, Department of Diabetology, Hôtel-Dieu Hospital (Paris), 1 place du Parvis de Notre-Dame 5ème A1, 75181 Paris Cedex 04, France. E-mail: taverna1{at}yahoo.fr.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The vitamin D (VD) receptor (VDR) is extensively expressed in retina. The plasma concentration of 1,25-dihydroxyvitamin D3 has been inversely correlated with the severity of diabetic retinopathy (DR), which raises the possibility that VD, through its antiinflammatory, antioxidant, antiproliferative, and antiangiogenic properties, may protect diabetic retina. The TaqI VDR polymorphism has been associated with severe DR. The FokI VDR polymorphism is a T-to-C substitution in the first codon (f allele), abolishing the first translation initiation site and resulting in a peptide lacking three amino acids (F allele), which increases the transcriptional activity of VDR.

Objective and Design: To examine whether FokI polymorphism is involved in severe DR, 254 Caucasians with longstanding C-peptide-negative type 1 diabetes, 128 patients with absent/mild DR (control group), and 126 patients with preproliferative/proliferative DR (study group) were genotyped using PCR-restriction fragment length polymorphism analysis.

Results: The genotype distribution was in Hardy-Weinberg equilibrium and was different between groups (P = 0.046). The frequency of F allele was significantly higher in the control (66.4%) than in the study group (56%, odds ratio = 0.64, 95% confidence interval 0.44–0.92, P = 0.016). In subjects with fewer than 25 yr of diabetes duration (median value, n = 134), this association was strongly increased (P = 0.0008).

Conclusions: In conclusion, we observed, in a cohort of Caucasians with C-peptide-negative type 1 diabetes, a novel association between the functional FokI VDR polymorphism and severe DR, especially among subjects with fewer than 25 yr of diabetes duration.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE DIABETES CONTROL and Complications Trial has highlighted that genetic factors could be implicated in the pathogenesis of severe diabetic retinopathy (DR) (1). Recently, we reported a novel genetic association between the TaqI vitamin D (VD) receptor (VDR) gene polymorphism and risk of severe DR (2). Several observations suggest that VDR could be a potential candidate gene for DR. The plasma concentration of 1,25-dihydroxyvitamin D3, the active VD, has been inversely correlated with the severity of DR in a Turkish cohort (3). In addition to its calciotropic function, the VD has potent nonclassical effects, including immunomodulatory, antiinflammatory, antioxidant, antiangiogenic, and antiproliferative properties (4, 5). All of them are mediated by VDR (6), a member of the nuclear receptor superfamily, which is extensively expressed in retina (7, 8).

The FokI VDR gene polymorphism is a functional T-to-C substitution in the first codon (f allele), abolishing the first translation initiation site and resulting in a peptide lacking the first three amino acids (F allele), which increases the transcriptional activity of VDR (9). This genetic marker can influence, among others, bone mineral density (9), serum PTH levels (10), susceptibility to prostate cancer (11), autoimmune diseases (type 1 diabetes, Graves’ disease, autoimmune hepatitis, etc.) (12, 13, 14), insulin secretion (15), and insulin sensitivity (16).

To examine whether the functional FokI VDR gene start codon polymorphism is involved in the risk of severe DR, a case-control study was carried out in Caucasian patients with longstanding C-peptide-negative type 1 diabetes.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
All patients recruited were unrelated French Caucasian patients living in the Paris area (Ile de France state), belonged to a medium socioeconomic status, and received regular health care. Ethnic minorities living in the Paris area as French Blacks (e.g. Africa), French Polynesian (e.g. Oceanic islands), and patients from French Antillas and Guyana were strictly excluded. All patients were regularly treated in our Department of Diabetology (including the Diabeto-Ophtalmology Unit), at the Hôtel-Dieu Hospital of Paris (France), had type 1 diabetes diagnosed before 35 yr (World Health Organization criteria), C-peptide-negative, and required permanent insulin therapy from the time of diabetes diagnosis. DR was evaluated according to the classification of the EURODIAB IDDM Complications Study (17). The control patients (nonsevere DR group; n = 128) had no DR (level 0; n = 39) or minimal nonproliferative DR (level 1; n = 89), with no antecedent of retinal laser photocoagulation. Patients with advanced DR (severe DR group; n = 126) had panretinal laser photocoagulation secondary to preproliferative DR (level 4; n = 34) or proliferative DR (level 5; n = 92). Individuals with intermediate DR forms, moderate nonproliferative DR (level 2), or severe nonproliferative DR (preproliferative DR) without laser photocoagulation (level 3) were strictly excluded. DR was evaluated by trained ophthalmologists of the Ophthalmo-Diabetology Unit of our hospital. To avoid diabetic patients being misclassified as having nonsevere DR because of a short duration of diabetes, we selected only control patients with a diabetes duration of more than 15 yr. There was no significant difference in either the mean age of diabetes or the mean duration of diabetes between the two groups. Clinical characteristics of subjects are given in Table 1Go. Diabetic nephropathy was assessed by albumin excretion rate (AER): normal AER (<30 mg/24 h; n = 167), microalbuminuria (30–300 mg/24 h; n = 43), macroalbuminuria (>300 mg/24 h; n = 44). To be classified as microalbuminuria or macroalbuminuria, AERs had to be elevated on at least two occasions in the absence of a urinary tract infection. The study was in agreement with the Declaration of Helsinki and had the approval of the ethics committee of our hospital. Informed consent was obtained from all participants. Serum levels of cholesterol, triglycerides, creatinine, and albumin urinary levels were measured by standard laboratory techniques. Serum C-peptide was measured by RIA (Double Antibody C-Peptide kit; Behring, EURO/DPC Ltd., Gwynedd, UK), and glycosylated hemoglobin (HbA1c) was measured by HPLC method (Diamat; Bio-Rad Laboratories, Inc., Hercules, CA).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical characteristics of subjects

 
Genotyping

Genotypes for FokI VDR polymorphism were scored blindly using PCR-restriction fragment length polymorphism analysis, as previously described (16). The following primers were used for PCR amplification of exon 2 of the VDR gene: forward 5'-AGCTGGCCCTGGCACTGACTCTGCTCT-3', and reverse 5'-ATGGAAACACCTTGCTTCTTCTCCCTC-3'. PCR products were digested with FokI (New England BioLabs, Inc., Beverly, MA) at 37 C for 3 h and then electrophoresed through a 3% agarose gel containing ethidium bromide. FokI digested the first ATG and yielded two products, 69 and 196 bp (f allele), whereas the T to C transition destroyed the FokI site (F allele). The FF and ff genotypes are also named CC and TT, respectively.

Statistical analyses

Data are expressed as means ± SD. The statistical difference in genotype distribution and allele frequencies among the groups was assessed by the {chi}2 test. Where appropriate, the odds ratio (OR) and 95% confidence interval (CI) estimating the relative risks of severe DR associated with FokI VDR polymorphism were calculated. Comparisons between the clinical characteristics of the two groups were made by unpaired t tests. A multivariate logistic regression analysis was performed to assess the independent role of the FokI VDR polymorphism and other variables [sex, age, age at onset, duration of diabetes, body mass index (BMI), blood pressure, HbA1c level, cholesterol level, smoking, renal function] on severe DR. The continuous variables, such as HbA1c and duration, were entered as linear factors after they were tested for nonlinearity by the use of the Box-Tidwell transformation (18). Because duration of diabetes is a crucial factor to be controlled in genetic studies of diabetic complications (19), the influence of FokI polymorphism on the risk of severe DR was analyzed according to different cutoffs of diabetes duration (e.g. control and case patients were stratified by mean diabetes duration, <25 and ≥25 yr). Taking the f allele frequency of 34% (20) and an OR of 2.5, this sample provided more than 95% power to detect an association (P < 0.05). Two-sided P < 0.05 was regarded as significant. Data analyses were performed with StatView version 4 (Abacus Concepts, Inc., Berkeley, CA). Taking into account that FokI single nucleotide polymorphism (SNP) can affect insulin sensitivity (16) and especially insulin secretion (15), we analyzed mediation models, using the tests of Sobel and Goodman (21), to detect whether a fraction of the influence of FokI VDR polymorphism on severe DR is mediated by HbA1c levels (program for Statistical Package for the Social Sciences, version 12.0 for Windows; SPSS, Inc., Chicago, IL). Mediation refers to the covariance relationships among three variables: an independent variable (IV), a potential mediating variable, and a dependent variable (DV). Mediation can be said to occur when the IV (FokI SNP) significantly affects the mediator (HbA1c levels), the IV significantly affects the DV (severe DR) in the absence of the mediator, the mediator has a significant unique effect on the DV, and the effect of the IV on the DV shrinks upon the addition of the mediator to the model (21).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
FokI VDR polymorphism and severe DR

Clinical characteristics of the study and control groups are given in Table 1Go. Genotype distributions in whole sample and in both study and control groups were in Hardy-Weinberg equilibrium (P = 0.99, P = 0.87, and P = 0.98, respectively) and did not differ between genders (P = 0.33, P = 0.26, and P = 0.82, respectively). The genotype distribution was FF, 37.4% (n = 95); Ff, 47.6% (n = 121); and ff, 15.0% (n = 38).

The distribution of FokI polymorphism was significantly different between groups ({chi}2 = 6.138; df = 2; P = 0.047). The frequency of FF genotype was significantly higher in individuals with mild or absent DR (n = 57; 44.5%) than in patients with severe DR (n = 38, 30.2%, {chi}2 = 5.602, df = 1, OR = 0.54, 95% CI 0.32–0.90, P = 0.018, corrected P = 0.025). The frequency of F allele was significantly higher in the control (n = 170; 66.4%) than in the study group (n = 141, 56.0%, {chi}2 = 5.846, df = 1, OR = 0.64, 95% CI 0.44–0.92, P = 0.016, corrected P = 0.020). The genotype and allele frequencies between groups are summarized in Table 2Go. Clinical characteristics (sex, age, age at diagnosis, duration of diabetes, BMI, HbA1c levels, smoking, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels, and renal function) between patients carrying the F allele and noncarrier patients were not significantly different (data not shown).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Genotype distribution and allele frequencies of FokI VDR polymorphism between groups (global {chi}2 test = 6.138, df = 2, P = 0.047)

 
Logistic regression analysis confirmed that FokI VDR polymorphism (FF genotype, OR = 0.39, 95% CI 0.18–0.83, P = 0.015), microalbuminuria (OR = 5.26, 95% CI 2.04–13.51, P = 0.0006), macroalbuminuria (OR = 14.60, 95% CI 3.14–67.77), P = 0.0006), HbA1c levels (OR = 1.89, 95% CI 1.42–2.51, P < 0.0001), and diastolic blood pressure (OR = 1.07, 95% CI 1.02–1.12, P = 0.0034) were the only IVs for severe DR (Table 3Go).


View this table:
[in this window]
[in a new window]
  		TABLE 3. Univariate and multivariate logistic regression analysis

 
Effect of duration of diabetes mellitus

Among case (n = 67) and control (n = 67) patients who had had diabetes for less than 25 yr (median value), the association between severe DR and FokI polymorphism was strongly increased ({chi}2 test = 11.447; df = 2; P = 0.003; Table 4Go). All groups were in Hardy-Weinberg equilibrium (P > 0.5).


View this table:
[in this window]
[in a new window]
  		TABLE 4. FokI VDR polymorphism in case and control patients with diabetes duration of < 25 yr ({chi}2 = 11.447, df = 2, P = 0.003) or ≥ 25 yr ({chi}2 test = 3.27, df = 2, P = 0.20)

 
Among case (n = 59) and control (n = 61) patients with diabetes duration ≥ 25 yr, the FokI polymorphism was not associated with severe DR ({chi}2 test = 3.270; df = 2; P = 0.20; Table 4Go). All groups were in Hardy-Weinberg equilibrium (P > 0.25).

We observed a significant interaction between diabetes duration and the association between FokI polymorphism and severe DR (P for interaction = 0.016).

FokI VDR polymorphism and HbA1c levels

In the whole sample (n = 254), the distribution of FokI polymorphism was not associated with HbA1c levels (ANOVA F = 0.69; P = 0.51).

Of note, among patients with diabetes duration of less than 25 yr (n = 134), the FokI polymorphism was significantly associated with HbA1c levels (ANOVA F = 3.82; P = 0.024). Specifically, FF-carriers had significantly lower HbA1c levels (8.28 ± 1.52%) than ff-carriers (9.34 ± 1.71%; P = 0.0073), and Ff-carriers had significantly lower HbA1c levels (8.50 ± 1.48%) than ff-carriers (P = 0.026). Also, among patients with diabetes of less than 30 yr (n = 187), FF-carriers had significantly lower HbA1c levels (8.30 ± 1.50%) than ff-carriers (9.01 ± 1.82%; P = 0.039).

According to the tests of Sobel and Goodman, in patients with diabetes duration less than 25 yr, HbA1c mediates 30.48% (P = 0.025) of the effects of FokI VDR SNP on severe DR (ratio of the indirect to the direct effect = 0.44). Contrary, in patients with diabetes duration of 25 yr or more, HbA1c only mediates 15.96% (P > 0.30) of the effects of FokI VDR SNP on severe DR (ratio of the indirect to the direct effect = 0.19).

FokI VDR polymorphism and diabetic nephropathy

The distribution of FokI polymorphism was not different among normoalbuminuric, microalbuminuric, and albuminuric patients ({chi}2 = 2.467; df = 4; P = 0.65). Diabetes duration did not influence this result (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first report that demonstrates a significant association between the FokI VDR gene polymorphism and the risk of advanced DR, in Caucasian patients with C-peptide-negative type 1 diabetes, especially among those patients with a duration of diabetes less than 25 yr. Specifically, patients carrying the F allele (or FF genotype) had a significantly lower prevalence of advanced DR. This finding was confirmed in multivariate statistical models.

Our findings are supported by several clinical and experimental observations. VD has osteocalcic, immunomodulatory, antiinflammatory, antioxidant, antiangiogenic, and antiproliferative functions in many kinds of cells, at both pharmacological and physiological levels (4, 5, 6). VD administration reduces angiogenesis, proliferation, and tumor size of retinoblastoma (22, 23, 24), and corneal inflammation and neovascularization (25, 26, 27). The plasma concentration of VD has been inversely correlated with the severity of DR (3). VDR is extensively expressed in retina (7, 8). VD increases insulin sensitivity and insulin secretion (28), and hyperglycemia down-regulates VDR (29) and renal 25-hydroxyvitamin D3–1 {alpha}-hydroxylase (30), the rate-limiting enzyme in the bioactivation of VD. Of note, the FF genotype of FokI VDR gene polymorphism has been associated with higher insulin secretion and insulin sensitivity, in nondiabetic Bangladeshi adults with VD insufficiency (15) and healthy Caucasians (16), respectively. We have reported a significant association between the T allele of TaqI VDR polymorphism and lower risk of advanced DR, especially among patients with long duration of diabetes and poor glycemic control (2). In nondiabetic Bangladeshi adults, both TT TaqI and FF FokI genotypes have been associated with the highest VDR mRNA copy numbers by 25.8% and 19.7%, compared with tt and ff genotypes (15).

Because the FF genotype (or F allele) of FokI polymorphism has been associated with increased transcriptional activity of VDR in most (9, 15, 31, 32), but not all, studies (33), we hypothesize that potential beneficial effects of VD on retina (e.g. immunomodulatory, antiinflammatory, antioxidant, antiangiogenic, and antiproliferative properties) were higher in patients carrying the F allele than in f-carrier patients, thus explaining the significant association between F allele and lower risk of advanced DR. In addition, we postulate that this finding was strongly increased in patients with a duration of diabetes less than 25 yr, in part because, among these individuals, but not in the whole sample, we detected significantly lower HbA1c levels in FF-carrier than in ff-carrier patients. Moreover, the Sobel and Goodman tests confirmed that, among patients with diabetes duration less than 25 yr, HbA1c mediated 30.48% of the effects of FokI VDR SNP on severe DR but only 15.96% among those patients with diabetes duration of 25 yr or more. This is in accordance with the fact that the FF genotype has been associated with both higher insulin secretion (15) and higher insulin sensitivity (16). Indeed, the duration of diabetes is a crucial factor to be controlled in genetic studies of diabetic complications (19). A susceptibility allele would be more strongly associated with affected individuals with a short duration, rather than a long duration, of diabetes (19, 34). Unquestionably, among patients with severe DR, despite the absence of one of the most important environmental factors (long duration of diabetes), other environmental factors (e.g. high HbA1c levels) as well as genetic factors must be overexpressed (e.g. FokI VDR SNP). The chance of spurious findings due to survival bias is unlikely, because we studied relatively young individuals. Indeed, there is no report showing an association between this polymorphism and heart disease.

We cannot exclude the possibility that the FokI VDR polymorphism site is a marker of a nearby functional polymorphism within the VDR gene or a nearby gene. Nevertheless, it has been reported among 68 VDR SNPs, including classical 3' polymorphisms (e.g. TaqI SNP, BsmI SNP, etc.), that FokI SNP, which is located in a 1.3-kb LD-breaking spot between two LD blocks, is the only SNP that has no detectable LD with any other SNP and cannot be assigned to any LD block in VDR (35). This scenario is supported by LD reports (www.hapmap.org) from the HapMap International Project (36). Thus, the FokI SNP could be the truly pathogenic VDR polymorphism for severe DR. On the other hand, the independence of FokI SNP can explain why haplotype-based analysis (combined effect of FokI and TaqI VDR SNPs) were not informative in our cohort (data not shown).

It is not surprising that, whereas the association of the FokI VDR SNP with severe DR was especially important among patients with a short duration of diabetes (<25 yr), a previous report showed that TaqI VDR SNP was preferentially associated with severe DR among patients with a long duration of diabetes (>25 yr). Taking into account that DR is a consequence of interactions between environmental and genetics factors, we hypothesize that, when the genetic influence is mild (the TaqI SNP appears to have only a mild or no effect on VDR) (37), the environmental exposure is stronger (long duration of diabetes). In the opposite picture, when the genetic participation is higher (the FokI SNP is the only VDR polymorphism that intensively affects the protein structure of VDR) (37), the development and progression of DR will require a lower environmental exposure (short duration of diabetes). This viewpoint is supported by multiple studies that have reported associations between important genetic alterations (e.g. deletions) and early onset of several conditions (38, 39, 40). This view requires further confirmation in prospective studies.

In molecular terms, VD can reduce nitric oxide production via inducible nitric oxide synthase down-regulation (41), inhibit vascular endothelial growth factor (VEGF) induced endothelial cell proliferation (42), down-regulate the IGF-I pathway (43), up-regulate the cellular transporters of sulfate (44) which are negative regulators of angiogenesis (45), down-regulate the renin-angiotensin system (46), stimulate the TGFß-1 (an antiproliferative and proapoptotic molecule) (47), and inhibit multiple proinflammatory and proangiogenic cytokines (4, 5, 6, 25, 26, 27). All of these molecules have been implicated in the pathogenesis of DR. On the other hand, calcium homeostasis and calcium-dependent signaling pathways have an important role in the development of retinal hypoxia (48), a major process in severe DR.

Can VD represent a major molecular link between kidney and retina? Patients with diabetic nephropathy have both a high risk of DR (49) and a high risk of low VD status (50). On the other hand, VD deficiency is associated with high plasma PTH levels. Contrary to VD, PTH excess can reduce glucose tolerance (51) and induce inflammatory cytokines (52). Interestingly, PTH is present in subretinal fluids of the human eye, and it was found high plasma PTH 44–68 levels (up to 4000 pg/ml) in patients with rhegmatogenous retinal detachments, especially among those with longstanding disease and proliferative vitreoretinopathy, including proliferative DR (53). Interestingly, a Czech study reported that serum PTH values were statistically higher in the ff than in the FF FokI VDR genotypes among Caucasian women with normal serum PTH levels (10).

At last, because human endothelia are able to produce active VD, in part via the rapid induction of endothelial 1{alpha}-OHase activity by inflammatory cytokines (54), potential local VD production in retinal endothelial cells is not unlikely and deserves to be investigated.

In conclusion, we have reported a novel association between the functional FokI VDR gene polymorphism and the risk of advanced DR in a well-characterized Caucasian cohort of patients with C-peptide-negative type 1 diabetes, especially among those patients with a duration of diabetes less than 25 yr, supported by a previous report showing an association between TaqI VDR polymorphism and severe DR.


   Footnotes
 
We thank C. Guyot-Argenton for assistance with ophthalmological examinations (Ophthalmo-Diabetology Unit, Hôtel-Dieu Hospital, Paris).

This study was supported by Association Française des Diabétiques and Aides aux Jeunes Diabétiques.

First Published Online May 17, 2005

Abbreviations: AER, Albumin excretion rate; BMI, body mass index; CI, confidence interval; DR, diabetic retinopathy; DV, dependent variable; HbA1c, glycosylated hemoglobin; IV, independent variable; OR, odds ratio; SNP, single nucleotide polymorphism; VD, vitamin D; VDR, VD receptor.

Received December 8, 2004.

Accepted May 5, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. The Diabetes Control and Complications Trial Research Group 1997 Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 46:1829–1839[Abstract]
  2. Taverna MJ, Sola A, Guyot-Argenton C, Pacher N, Bruzzo F, Slama G, Reach G, Selam JL 2002 Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy. Diabetologia 45:436–442[CrossRef][Medline]
  3. Aksoy H, Akcay F, Kurtul N, Baykal O, Avci B 2000 Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D (25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem 33:47–51[CrossRef][Medline]
  4. Reichel H, Koeffler HP, Norman AW 1989 The role of the vitamin D endocrine system in health and disease. N Engl J Med 320:980–991[Medline]
  5. Lin R, White JH 2004 The pleiotropic actions of vitamin D. Bioessays 26:21–28[CrossRef][Medline]
  6. Carlberg C 2003 Current understanding of the function of the nuclear vitamin D receptor in response to its natural and synthetic ligands. Recent Results Cancer Res 164:29–42[Medline]
  7. Schreiner DS, Jande SS, Lawson DE 1985 Target cells of vitamin D in the vertebrate retina. Acta Anat (Basel) 121:153–162[Medline]
  8. Johnson JA, Grande JP, Roche PC, Campbell RJ, Kumar R 1995 Immunolocalization of the calcitriol receptor, calbindin-D28k and the plasma membrane calcium pump in the human eye. Curr Eye Res 14:101–108[Medline]
  9. Jurutka PW, Remus LS, Whitfield GK, Thompson PD, Hsieh J-C, Zitzer H, Tavakkoli P, Galligan MA, Dang HTL, Haussler CA, Haussler MR 2000 The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. Mol Endocrinol 14:401–420[Abstract/Free Full Text]
  10. Zofkova I, Zajickova K, Hill M 2003 Serum parathyroid hormone levels are associated with FokI polymorphism of the vitamin D receptor gene in untreated postmenopausal women. Eur J Intern Med 14:232–236[Medline]
  11. Bodiwala D, Luscombe CJ, French ME, Liu S, Saxby MF, Jones PW, Fryer AA, Strange RC 2004 Polymorphisms in the vitamin D receptor gene, ultraviolet radiation, and susceptibility to prostate cancer. Environ Mol Mutagen 43:121–127[CrossRef][Medline]
  12. Ban Y, Taniyama M, Yanagawa T, Yamada S, Maruyama T, Kasuga A, Ban Y 2001 Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population. BMC Med Genet 2:7[CrossRef][Medline]
  13. Ban Y, Ban Y, Taniyama M, Katagiri T 2000 Vitamin D receptor initiation codon polymorphism in Japanese patients with Graves’ disease. Thyroid 10:375–380[Medline]
  14. Fan L, Tu X, Zhu Y, Zhou L, Pfeiffer T, Feltens R, Stoecker W, Zhong R 2005 Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese. J Gastroenterol Hepatol 20:249–255[CrossRef][Medline]
  15. Ogunkolade BW, Boucher BJ, Prahl JM, Bustin SA, Burrin JM, Noonan K, North BV, Mannan N, McDermott MF, DeLuca HF, Hitman GA 2002 Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes 51:2294–2300[Abstract/Free Full Text]
  16. Chiu KC, Chuang LM, Yoon C 2001 The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians. BMC Med Genet 2:2[CrossRef][Medline]
  17. Aldington SJ, Kohner EM, Meuer S, Klein R, Sjolie AK 1995 Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM Complications Study. Diabetologia 19:437–444
  18. Box GEP, Tidwell PW 1962 Transformations of the independent variables. Technometrics 4:531–550[CrossRef]
  19. Rogus JJ, Warram JH, Krolewski AS 2002 Genetic studies of late diabetic complications: the overlooked importance of diabetes duration before complication onset. Diabetes 51:1655–1662[Abstract/Free Full Text]
  20. Correa-Cerro L, Berthon P, Haussler J, Bochum S, Drelon E, Mangin P, Fournier G, Paiss T, Cussenot O, Vogel W 1999 Vitamin D receptor polymorphisms as markers in prostate cancer. Hum Genet 105:281–287[CrossRef][Medline]
  21. Dudley WN, Benuzillo JG, Carrico MS 2004 SPSS and SAS programming for the testing of mediation models. Nurs Res 53:59–62[CrossRef][Medline]
  22. Saulenas AM, Cohen SM, Key LL, Winter C, Albert DM 1988 Vitamin D and retinoblastoma. The presence of receptors and inhibition of growth in vitro. Arch Ophthalmol 106:533–535[Abstract/Free Full Text]
  23. Audo I, Darjatmoko SR, Schlamp CL, Lokken JM, Lindstrom MJ, Albert DM, Nickells RW 2003 Vitamin D analogues increase p53, p21, and apoptosis in a xenograft model of human retinoblastoma. Invest Ophthalmol Vis Sci 44:4192–4199[Abstract/Free Full Text]
  24. Wagner N, Wagner KD, Schley G, Badiali L, Theres H, Scholz H 2003 1,25-Dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. Exp Eye Res 77:1–9[CrossRef][Medline]
  25. Suzuki T, Sano Y, Kinoshita S 2000 Effects of 1{alpha},25-dihydroxyvitamin D3 on Langerhans cell migration and corneal neovascularization in mice. Invest Ophthalmol Vis Sci 41:154–158[Abstract/Free Full Text]
  26. Suzuki T, Sano Y, Sotozono C, Kinoshita S 2000 Regulatory effects of 1{alpha},25-dihydroxyvitamin D(3) on cytokine production by human corneal epithelial cells. Curr Eye Res 20:127–130[CrossRef][Medline]
  27. Xue ML, Zhu H, Thakur A, Willcox M 2002 1-{alpha},25-Dihydroxyvitamin D3 inhibits pro-inflammatory cytokine and chemokine expression in human corneal epithelial cells colonized with Pseudomonas aeruginosa. Immunol Cell Biol 80:340–345[CrossRef][Medline]
  28. Chiu KC, Chu A, Go VL, Saad MF 2004 Hypovitaminosis D is associated with insulin resistance and ß-cell dysfunction. Am J Clin Nutr 79:820–825[Abstract/Free Full Text]
  29. Ishida H, Cunningham NS, Henry HL, Norman AW 1988 The number of 1,25-dihydroxyvitamin D3 receptors is decreased in both intestine and kidney of genetically diabetic db/db mice. Endocrinology 122:2436–2443[Abstract/Free Full Text]
  30. Spencer EM, Khalil M, Tobiassen O 1980 Experimental diabetes in the rat causes an insulin-reversible decrease in renal 25-hydroxyvitamin D3–1{alpha}-hydroxylase activity. Endocrinology 107:300–305[Abstract/Free Full Text]
  31. Colin EM, Weel AE, Uitterlinden AG, Buurman CJ, Birkenhager JC, Pols HA, van Leeuwen JP 2000 Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1,25-dihydroxyvitamin D3. Clin Endocrinol (Oxf) 52:211–216[CrossRef][Medline]
  32. Arai H, Miyamoto K, Taketani Y, Yanamoto H, Iemori Y, Morita K, Tonai T, Nishisho T, Mori S, Takeda E 1997 A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women. J Bone Miner Res 12:915–921[CrossRef][Medline]
  33. Gross C, Krishnan AV, Malloy PJ, Eccleshall TR, Zhao XY, Feldman D 1998 The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. J Bone Miner Res 13:1691–1699[CrossRef][Medline]
  34. Canani LH, Ng DPK, Smiles A, Rogus JJ, Warram JH, Krolewski AS 2002 Polymorphism in ecto-nucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1/PC-1) and early development of advanced diabetic nephropathy in type 1 diabetes. Diabetes 51:1188–1193[Abstract/Free Full Text]
  35. Nejentsev S, Godfrey L, Snook H, Rance H, Nutland S, Walker NM, Lam AC, Guja C, Ionescu-Tirgoviste C, Undlien DE, Ronningen KS, Tuomilehto-Wolf E, Tuomilehto J, Newport MJ, Clayton DG, Todd JA 2004 Comparative high-resolution analysis of linkage disequilibrium and tag single nucleotide polymorphisms between populations in the vitamin D receptor gene. Hum Mol Genet 13:1633–1639[Abstract/Free Full Text]
  36. The International HapMap Consortium 2003 The International HapMap Project. Nature 426:789–796[CrossRef][Medline]
  37. Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP 2004 Genetics and biology of vitamin D receptor polymorphisms. Gene 338:143–156[CrossRef][Medline]
  38. Tsai YY, Lee H, Tseng SH, Cheng YW, Tsai CH, Wu YH, Tsai FJ 2004 Null type of glutathione S-transferase M1 polymorphism is associated with early onset pterygium. Mol Vis 10:458–461[Medline]
  39. Raja SM, Chhablani N, Swanson R, Thompson E, Laffan M, Lane DA, Olson ST 2003 Deletion of P1 arginine in a novel antithrombin variant (antithrombin London) abolishes inhibitory activity but enhances heparin affinity and is associated with early onset thrombosis. J Biol Chem 278:13688–13695[Abstract/Free Full Text]
  40. Zhang H, Ping XL, Lee PK, Wu XL, Yao YJ, Zhang MJ, Silvers DN, Ratner D, Malhotra R, Peacocke M, Tsou HC 2001 Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol 158:381–385[Abstract/Free Full Text]
  41. Chang JM, Kuo MC, Kuo HT, Hwang SJ, Tsai JC, Chen HC, Lai YH 2004 1-{alpha},25-Dihydroxyvitamin D3 regulates inducible nitric oxide synthase messenger RNA expression and nitric oxide release in macrophage-like RAW 264.7 cells. J Lab Clin Med 143:14–22[Medline]
  42. Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE 2000 1{alpha},25-Dihydroxyvitamin D(3) inhibits angiogenesis in vitro and in vivo. Circ Res 87:214–220[Abstract/Free Full Text]
  43. Sprenger CC, Peterson A, Lance R, Ware JL, Drivdahl RH, Plymate SR 2001 Regulation of proliferation of prostate epithelial cells by 1,25-dihydroxyvitamin D3 is accompanied by an increase in insulin-like growth factor binding protein-3. J Endocrinol 170:609–618[Abstract]
  44. Bolt MJ, Liu W, Qiao G, Kong J, Zheng W, Krausz T, Cs-Szabo G, Sitrin MD, Li YC 2004 Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate co-transporter by 1,25-dihydroxyvitamin D3. Am J Physiol Endocrinol Metab 287:E744–E749
  45. Presta M, Leali D, Stabile H, Ronca R, Camozzi M, Coco L, Moroni E, Liekens S, Rusnati M 2003 Heparin derivatives as angiogenesis inhibitors. Curr Pharm Des 9:553–566[CrossRef][Medline]
  46. Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J 2004 Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 89–90:387–392
  47. Bizzarri M, Cucina A, Valente MG, Tagliaferri F, Borrelli V, Stipa F, Cavallaro A 2003 Melatonin and vitamin D3 increase TGF-ß1 release and induce growth inhibition in breast cancer cell cultures. J Surg Res 110:332–337[CrossRef][Medline]
  48. Osborne NN, Casson RJ, Wood JP, Chidlow G, Graham M, Melena J 2004 Retinal ischemia: mechanisms of damage and potential therapeutic strategies. Prog Retin Eye Res 23:91–147[CrossRef][Medline]
  49. Vigstrup J, Mogensen CE 1985 Proliferative diabetic retinopathy: at risk patients identified by early detection of microalbuminuria. Acta Ophthalmol (Copenh) 63:530–534
  50. Ishimura E, Nishizawa Y, Inaba M, Matsumoto N, Emoto M, Kawagishi T, Shoji S, Okuno S, Kim M, Miki T, Morii H 1999 Serum levels of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in nondialyzed patients with chronic renal failure. Kidney Int 55:1019–1027[CrossRef][Medline]
  51. Procopio M, Borretta G 2003 Derangement of glucose metabolism in hyperparathyroidism. J Endocrinol Invest 26:1136–1142[Medline]
  52. Mitnick MA, Grey A, Masiukiewicz U, Bartkiewicz M, Rios-Velez L, Friedman S, Xu L, Horowitz MC, Insogna K 2001 Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor. Am J Physiol Endocrinol Metab 280:E405–E412
  53. Bialasiewicz AA, Atkinson MJ, Hesch RD 1985 Immunoreactive parathyroid hormone is present in subretinal fluids of the human eye. Curr Eye Res 4:619–625[Medline]
  54. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M 2002 Synthesis of 1,25-dihydroxyvitamin D(3) by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. J Am Soc Nephrol 13:621–629[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Reproductive SciencesHome page
A. Agic, Hong Xu, C. Altgassen, F. Noack, M. M. Wolfler, K. Diedrich, M. Friedrich, R. N. Taylor, and D. Hornung
Relative Expression of 1,25-Dihydroxyvitamin D3 Receptor, Vitamin D 1{alpha}-Hydroxylase, Vitamin D 24-Hydroxylase, and Vitamin D 25-Hydroxylase in Endometriosis and Gynecologic Cancers
Reproductive Sciences, July 1, 2007; 14(5): 486 - 497.
[Abstract] [PDF]

Home page
 Hum Mol GenetHome page
A. Dempfle, S. A. Wudy, K. Saar, S. Hagemann, S. Friedel, A. Scherag, L. D. Berthold, G. Alzen, L. Gortner, W. F. Blum, et al.
Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies
Hum. Mol. Genet., September 15, 2006; 15(18): 2772 - 2783.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Taverna, M. J.
Right arrow Articles by Slama, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Taverna, M. J.
Right arrow Articles by Slama, G.
Related Collections
Right arrow Calcium and Bone Metabolism
Right arrow Diabetes and Insulin

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals