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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3137-3140
Copyright © 2003 by The Endocrine Society

Vitamin D Receptor Gene Polymorphism Affects Onset Pattern of Type 1 Diabetes

Yoshiko Motohashi, Satoru Yamada, Tatsuo Yanagawa, Taro Maruyama, Ryuji Suzuki, Masaaki Niino, Toshiyuki Fukazawa, Akira Kasuga, Hiroshi Hirose, Koichi Matsubara, Akira Shimada and Takao Saruta

Department of Internal Medicine (Y.M., S.Y., R.S., H.H., A.S., T.S.), Keio University School of Medicine, Tokyo 160-8582; Department of Internal Medicine (T.Y.), Nerima General Hospital, Tokyo 176-8583; Department of Internal Medicine (T.M.), Saitama Social Insurance Hospital, Saitama 336-0002; Department of Neurology (M.N.), Hokkaido University Graduate School of Medicine, Sapporo 060-8638; Hokuyukai Neurology Hospital (T.F.), Sapporo 063-0802; Department of Internal Medicine (A.K.), Tokyo Denryoku Hospital, Tokyo 160-0016; and Chugai Diagnostic Science Research Center (K.M.), Tokyo 104-8301, Japan

Address all correspondence and requests for reprints to: Yoshiko Motohashi, M.D., 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: asmd{at}sc.itc.keio.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
MOST TYPE 1 diabetes in humans is considered to be a T-cell-mediated autoimmune disease (1). In an animal model of T-cell-mediated autoimmune diabetes (2, 3, 4), it has been reported that administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3] suppressed the incidence of diabetes, probably by modulating the T-helper (Th)1/Th2 cytokine balance in the local pancreatic lesion (5). Recent studies have clarified the molecular basis of the immunomodulatory activity of 1,25(OH)2 D3 (6), and its specific nuclear receptors are known to be present on monocytes and activated T lymphocytes (7, 8). This hormone inhibits T-cell activation both in vitro and in vivo and inhibits secretion of cytokines such as IL-1, IL-2, IL-6, IL-12, TNF, and interferon-{gamma} (9, 10, 11), which are believed to be involved in the pathogenesis of autoimmune diseases (12).

We, therefore, investigated a vitamin D receptor (VDR) gene polymorphism in type 1 diabetes, considering the possibility that this gene may affect the pathophysiology of this disease. Moreover, we stratified type 1 diabetics according to their onset pattern and assessed its relationship to the VDR gene polymorphism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and controls

Two hundred three Japanese type 1 diabetic patients [mean onset age, 34.6 ± 16.9 (range, 1–78) yr old; 96 men and 107 women] and 222 unrelated healthy subjects [44.4 ± 13.7 (range, 20–72) yr old, 101 men and 121 women] were recruited for this study. Informed consent was obtained from all of the subjects, and institutional review board approval was obtained.

In a subpopulation study, we defined group A as acute-onset type 1 diabetics without islet-associated autoantibody, group B as acute-onset type 1 diabetics with islet-associated autoantibody, and group C as slow-onset type 1 diabetics with islet-associated autoantibody.

The diagnosis of acute-onset type 1 diabetes was made based on the criteria of the American Diabetes Association for type 1 diabetes; that is, pancreatic ß-cell destruction as the primary cause of the disorder and a tendency toward ketoacidosis (13), and the period from diabetes onset to insulin treatment was less than 6 months. Slow-onset type 1 diabetes was diagnosed based on islet-associated autoantibody positivity, and the period from diabetes onset to insulin treatment was more than 12 months, in this study. The healthy subjects were confirmed to have normal glucose tolerance, no autoimmune disease, no autoantibodies, and no family history of diabetes mellitus.

Autoantibody measurement

Screening for anti-GAD65 antibody (GADA) was performed using a recombinant human GAD65 kit (RSR Ltd., Cardiff, UK), and "positive" was defined as a value above mean +3 SD of that in healthy subjects (an index greater than 1.3 U/ml). Screening for IA-2 antibody (an index more than 0.010) and insulin autoantibody (IAA) (>50 nU/ml) was performed as previously described (14, 15). When at least one of GADA, IA-2 antibody, and IAA was positive, those patients were defined as "islet-associated autoantibody positive," although none of the patients were positive for IAA only.

Analysis of VDR-BsmI polymorphism

After obtaining informed consent from the recruited subjects, we extracted DNA from peripheral blood. Referring to the VDR gene sequence (accession no. I33554), PCR amplification of the region containing the polymorphism was performed using the forward primer in exon 7 (5'-CAACCAAGACTACAAGTACCGCGTCAGTGA-3') and the reverse primer in intron 8 (5'-AACCAGCGGGAAGAGGTCAAGGG-3'). The PCR conditions used in this study were as follows: 95 C for 5 min, and 30 cycles using the following temperature profile: 95 C for 1 min, 56 C for 1 min, 72 C for 1 min, and final elongation for 10 min. The PCR products were 825-bp long (B allele) and were digested with Bsm I at 65 C for 1 h, and then subjected to electrophoresis in 2% agarose gel containing ethidium bromide. The lengths of the restriction fragments were 649 and 176 bp (b allele). Genotype was determined from the lengths of fragments, i.e. BB, Bb, and bb (PCR-restriction-fragments-of-length-polymorphism method) (16).

Human lymphocyte antigen (HLA) typing

HLA type was examined by the hybridization protection assay, an HLA typing method based on hybridization of acridium-ester-labeled DNA probes to amplified DNA, as described previously (17).

Statistical analysis

Comparisons of genotype frequency and allele frequency between groups were performed using Fisher’s exact test. The Bonferroni correction for multiple comparisons was performed, where appropriate.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
First of all, the VDR-Bsm I polymorphism was compared between type 1 diabetic patients overall and healthy subjects. In healthy subjects, the distribution of genotypes was not significantly different from the expectation under Hardy-Weinberg equilibrium. The genotype frequency of carriers of B allele in type 1 diabetic patients was significantly higher than that in the controls (P = 0.0010). In the analysis of allele frequencies, there was a significantly higher frequency of B allele in type 1 diabetics overall, compared with the controls as well (P < 0.0001) (Table 1Go).


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  		TABLE 1. Distribution of VDR gene polymorphism in patients with type 1 diabetes overall and controls

 
Moreover, acute-onset type 1 diabetics had a higher frequency of B allele, compared with slow-onset type 1 diabetics. The frequency of B allele in slow-onset type 1 diabetics was not significantly different from that in controls (Table 2Go).


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  		TABLE 2. Relation between VDR gene polymorphism and onset pattern

 
In acute-onset patients, regardless of the existence of islet-associated autoantibody, there was a significant difference in B allele frequency between type 1 diabetics and controls (Tables 3Go and 4Go).


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  		TABLE 3. VDR gene polymorphism in subgroups of patients with type 1 diabetes

 

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  		TABLE 4. VDR gene polymorphism in subgroups of patients with type 1 diabetes

 
In the Japanese population, HLA DR4 and DR9 are considered to be major susceptible genes for type 1 diabetes (17), and Kobayashi et al. reported that the frequencies of HLA A24 and Bw54 were different between acute-onset type 1 diabetics and slow-onset diabetics (18). Therefore, we also examined such HLA types in a part of the recruited subjects. The prevalence of HLA-DR4 in acute and slow-onset patients was 62.3% and 54.3%, respectively. Similarly, the prevalence of other HLA types (HLA-DR9, A24, and Bw54) in acute and slow-onset patients was 49.2% and 47.8%, 69.6% and 51.2%, and 34.8%, and 19.5%, respectively; and there was no significant difference between acute-onset and slow-onset type 1 diabetics regarding these HLA types in this study. Although the frequencies of HLA A24 and Bw54 in acute-onset type 1 diabetics were higher than those in slow-onset type 1 diabetics, the differences did not reach statistical significance in our study.

Moreover, there was no significant difference regarding the prevalence of the HLA types in each subgroup (groups A, B, and C) as well. Regardless of the presence or absence of each HLA type (DR4, DR9, A24, or Bw54), the distribution of genotype frequencies in type 1 diabetic patients was consistent.

Moreover, onset age did not affect the distribution of genotype frequencies in type 1 diabetic patients, because there was no significant difference between patients above and below the mean onset age in each subgroup (groups A, B, and C). Sex did not affect the distribution of genotype frequencies in each subgroup as well. Finally, in healthy subjects also, age and sex did not affect the distribution of genotype frequencies.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study demonstrated a significantly higher frequency of B allele in type 1 diabetics overall, compared with the controls. Moreover, acute-onset type 1 diabetics had a higher frequency of B allele than the controls, whereas this was not the case in slow-onset type 1 diabetics.

Recently, some VDR gene polymorphisms were shown to be associated with autoimmune diseases (19, 20, 21, 22, 23, 24, 25, 26, 27). In studies of type 1 diabetes in Taiwanese, it has been shown that type 1 diabetes was associated with B allele (19). In Southern Indian families, preferential transmission of the b allele to affected subjects was observed, although it was not concluded whether the association was strictly with the b allele itself (20). Also, in the VDR-Fok I polymorphism, the F allele seemed to predispose to diabetes; and in the VDR-Taq I polymorphism, the T allele seemed to be protective in Romanian type 1 diabetics (26). Therefore, the susceptible allele of this gene and the significance of this gene in type 1 diabetes are still controversial. Tien-Jyun Chang et al. (19) studied the relationship of the VDR gene polymorphism to autoantibodies (GADA, IA-2 antibody) and found no significant relationship among them. However, in their study, the clinical course, such as onset pattern, was not taken into account, which might be one of the reasons for the difference between the results of their report and ours.

Some investigators have tried to reveal a genetic difference between acute-onset and slow-onset type 1 diabetes, by HLA types. For instance, Kobayashi et al. (18) reported that the frequencies of HLA A24 and Bw54 were different between acute-onset and slow-onset diabetics. In the Japanese population, HLA DR4 and DR9 are considered to be major susceptible genes for type 1 diabetes (17). Therefore, we focused on these four HLA types in relation to the VDR gene in this study. The distributions of DR4 and DR9 were not significantly different between acute-onset and slow-onset type 1 diabetics in this study. The frequencies of HLA A24 and Bw54 in acute-onset type 1 diabetics were higher than those in slow-onset type 1 diabetics, but the differences did not reach statistical significance in our study. When we analyzed the distribution of the VDR gene polymorphism in each HLA type, regardless of the presence or absence of these HLA types, the distributions of genotype and allele frequencies of the VDR gene among type 1 diabetics were consistent. Therefore, we concluded that the VDR gene polymorphism is related to type 1 diabetes independent of HLA types.

In Japanese subjects with multiple sclerosis, the frequency of bb genotype was found to be higher than in healthy subjects (22), and it was suggested that bb genotype may affect the development of autoimmune phenomena, leading to multiple sclerosis. Taking these findings, together with our results, the effect of VDR genotype on autoimmune disease may differ among target organs.

We found an association between the VDR gene polymorphism and acute-onset type 1 diabetes, regardless of the presence or absence of islet-associated autoantibody. However, it has not yet been established whether the pathophysiology in acute-onset diabetic patients with islet-associated autoantibody can be considered the same as that in acute-onset diabetes without islet-associated autoantibody. Recently, we have reported that GAD-reactive interferon-{gamma}-producing CD4+ cells existed in at least half of acute-onset type 1 diabetics, even in those without islet-associated autoantibody (28). By assessing the existence of islet-antigen-reactive T cells in the peripheral blood from those patients, it may be possible to evaluate the pathophysiology in relation to the VDR gene polymorphism in a future study.

Recently, we have proposed the hypothesis that differences in the degree of regeneration of pancreatic islet cells may be associated with the onset pattern of type 1 diabetes, and we examined a polymorphism of the Neuro D/BETA 2 gene (29), which is considered to be associated with regeneration of pancreatic islet cells (30), in type 1 diabetes. In our previous study (29), the distribution of genotype frequencies in acute-onset type 1 diabetic patients seemed to differ from that in slow-onset type 1 diabetic patients, regardless of autoantibody positivity. Comparing the data between our previous Neuro D/BETA 2 study and our present VDR study, both the Neuro D/BETA 2 gene and VDR gene seem to affect the onset pattern. Among subjects with GG genotype of the Neuro D/BETA 2 gene, which is considered to be unrelated to the acute-onset pattern, acute-onset subjects had a higher frequency of B allele of the VDR gene than did slow-onset subjects, although the difference did not reach statistical significance (data not shown). Considering these results, we speculate that the regeneration of pancreatic islet cells and immunoregulatory effects may independently influence the pathophysiology of type 1 diabetes, although accumulation of more data is needed to reach a conclusion.

In non-obese diabetic (NOD) mice, an excellent animal model of human type 1 diabetes (2, 3, 4), long-term treatment with high doses of 1,25(OH)2 D3 reduced the incidence of diabetes by changing the cytokine balance at the local pancreatic lesion, without major side effects (5). Moreover, 1,25(OH)2 D3 could prevent the recurrence of autoimmune disease after syngeneic islet transplantation (31, 32), and administration of GAD65 and 1,25(OH)2 D3 to NOD mice changed the autoantigen-specific cytokine balance in this model (33). Short-term treatment of adult NOD mice with an analog of 1,25(OH)2 D3 (3) inhibited IL-12 production, blocked pancreatic infiltration of Th1 cells, and arrested the progression of type 1 diabetes, suggesting its possible application in the treatment of human autoimmune diabetes (34). Interestingly, a recent epidemiological study from several European countries revealed that vitamin D supplementation in early childhood seems to be associated with a reduction in the incidence of type 1 diabetes (35). The immunoregulatory effects of vitamin D administration through VDRs might modulate the disease course of type 1 diabetes. We speculate that the effects of vitamin D administration, through VDRs, may be affected by VDR gene polymorphisms. Therefore, by assessing the genotype of the VDR gene polymorphism, it may be possible to select individuals in the population in whom the onset of type 1 diabetes might be prevented by vitamin D supplementation.

In conclusion, the VDR-Bsm I polymorphism is associated with acute-onset type 1 diabetes in Japanese. Assessment of VDR gene polymorphisms may contribute to prediction of the onset pattern in the high-risk group for type 1 diabetes.


   Footnotes
 
Y.M. and S.Y. contributed equally to this work.

Abbreviations: GADA, anti-GAD65 antibody; HLA, human lymphocyte antigen(s); IAA, insulin autoantibody; NOD, non-obese diabetic; 1,25(OH)2 D3, 1,25-dihydroxy vitamin D3; Th, T-helper; VDR, vitamin D receptor.

Received November 30, 2002.

Accepted March 21, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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