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Vitamin D Receptor Gene Polymorphism Is Associated with Graves’ Disease in the Japanese Population¹

Third Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan

Address all correspondence and requests for reprints to: Dr. Yoshiyuki Ban, Third Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa, Tokyo 142-8666, Japan. E-mail: yshsban{at}ns2.cc.showa-u.ac.jp

	Abstract

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Susceptibility to Graves’ disease (GD), which is determined by environmental and genetic factors, is conferred by genes in the human leukocyte antigen (HLA) and genes unlinked to HLA, including the CTLA-4 gene. We recently described the association of GD with the vitamin D receptor (VDR) exon 2 initiation codon (VDR-FokI) polymorphism. An association of some VDR genotypes with osteoporosis, primary hyperparathyroidism, and some autoimmune diseases, such as insulin-dependent diabetes mellitus and multiple sclerosis, has been reported. We investigated the distribution of VDR gene polymorphism in 180 Japanese patients with GD (48 males and 132 females) and 195 controls (67 males and 128 females). A VDR allelic polymorphism was assessed by BsmI endonuclease restriction after specific PCR amplification. Genotypic polymorphism was clearly defined as BB (no restriction site on both alleles), bb (restriction site on both alleles), or Bb (heterozygous). The distribution of genotype frequencies differed between patients with GD and controls (² = 7.53; 2 degrees of freedom; P = 0.023). The relative risk conferred by at least 1 B allele (BB or Bb) was 1.5. We also found an association between VDR-ApaI polymorphism and GD. No relation was detected between this polymorphism and the VDR-FokI polymorphism in the patients. The present results support the association of the VDR gene with GD in Japanese by showing that the VDR gene could be a non-HLA-linked gene predisposing an individual to GD. The role of the VDR gene polymorphism should be further studied in other populations, and the distribution of other polymorphisms, such as the polyadenylase polymorphism further down the VDR 3'-untranslated region, should be studied in terms of GD susceptibility.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GRAVES’ DISEASE (GD) is an autoimmune thyroid disease in which TSH receptor autoantibodies cause hyperthyroidism (1, 2, 3). The etiology of the disease involves an interaction between genetic and environmental factors (1, 2, 3). Genetic susceptibility to GD is conferred by the human leukocyte antigen (HLA) class II gene, located on chromosome 6q21 (1, 2, 3, 4, 5, 6), and the CTLA-4 gene, located on chromosome 2q33 (6, 7, 8, 9, 10). We recently reported that the vitamin D receptor (VDR) exon 2 initiation codon (VDR-FokI) polymorphism on chromosome 12q12–12q14 is associated with GD in the Japanese (11).

The human VDR gene has eight coding exons and three alternative 5'-noncoding exons spanning over 75 kb of DNA on chromosome 12q12–12q14 (12). VDR belongs to the nuclear hormone receptor superfamily and modulates the transcription of target genes in response to 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] (13), a potent immunomodulatory hormone. There are five known polymorphisms in the VDR locus: the exon 2 initiation codon polymorphism, detected by the FokI restriction enzyme (14), a cluster of polymorphisms in the 3'-end of the VDR gene, defined by the restriction enzymes BsmI, ApaI, and TaqI (15), and the polyadenylase polymorphism further down the VDR 3'-untranslated region (16, 17). No linkage disequilibrium is apparent between the BsmI, ApaI, and TaqI polymorphisms and the VDR-FokI polymorphism (18, 19, 20). The ApaI polymorphism is linked to the BsmI polymorphism (75% linkage), whereas the TaqI polymorphism is in a strong linkage disequilibrium with the BsmI polymorphism (12, 15).

Associations between VDR-BsmI polymorphism and osteoporosis (12, 15), primary hyperparathyroidism (pHPT) (21, 22), and some autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM) (23) and multiple sclerosis (MS) (24), have been reported. To confirm genetic susceptibility to GD and to improve GD treatment strategies, we examined BsmI and ApaI gene polymorphisms in Japanese patients with GD and in controls.

	Subjects and Methods

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Subjects

One hundred and eighty unrelated Japanese patients with GD (48 males and 132 females) were included in this study. GD was diagnosed on the basis of clinical symptoms and biochemical confirmation of hyperthyroidism, such as a diffuse goiter, ophthalmopathy, elevated radioactive iodine uptake, and thyroid hormone levels. One hundred and ninety-five unrelated Japanese adults (67 males and 128 females) without clinical evidence or family history of autoimmune disease were selected as normal local controls. The effects of the VDR-BsmI genotype on 1,25-(OH)₂D₃ were investigated in the 37 GD patients in remission (age range, 47–78 yr), none of whom had been treated with radioiodine, surgery, or drugs that could affect bone turnover or bone mineral density (BMD) before the study. Remission of Graves’ disease is defined as follows: both TSH receptor antibody and thyroid-stimulating antibody in a negative range for 6 months, and a subsequent relatively stable euthyroid state over at least 6 months after cessation of antithyroid drug treatment. Remission ranged from 0.5–22.0 yr. Informed consent was obtained from patients and controls. The research protocol was approved by the ethics committee of our hospital.

Measurement of 1,25-(OH)₂D₃

Blood samples were collected in the early morning after an overnight fast. Sera were stored at -70 C for measurement. Serum 1,25-(OH)₂D₃ was measured by RIA (SRL Co., Tokyo, Japan). The intra- and interassay coefficients of variation were within 10% for this assay.

Genotype analysis

Genomic DNA was isolated from whole blood with a Genomix kit (Talent, Trieste, Italy). The VDR gene was amplified with PCR. Detection of the BsmI site was achieved by amplifying a region spanning the site with one primer originating in exon 7 (primer 1, 5'-GGGAGACGTAGCAAAAGG-3') and the other in intron 8 (primer 2, 5'-AGAGGTCAAGGGTCACTG-3') producing a 359-bp fragment. Detection of the ApaI site was facilitated with the use of a single amplification with one primer in intron 8 (primer 3, 5'-CAGAGCATGGACAGGGAGCAAG-3') and the other in exon 9 (primer 4, 5'-GCAACTCCTCATGGCTGAGGTCTCA-3'), producing a 740-bp fragment. Each sample was subjected to 30 amplification cycles of fast capillary PCR performed with an FTS-1 thermocycler (Corbett Research, Sydney, Australia). The restriction fragment length polymorphisms (RFLPs) were coded as Bb (BsmI) or Aa (ApaI); uppercase letters signify the absence of the site, and lowercase letters signify the presence of the site.

Statistical analysis

Genotypes and alleles in patients and controls were compared with the ² test for two by two, two by three, and three by three tables and by Fisher’s exact test. The relative risk was calculated with Woolf’s method (25). Student’s t test was used to compare serum 1,25-(OH)₂D₃ levels among the GD patients in remission. All values are presented as the mean ± SD. P < 0.05 was considered significant.

	Results

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Genotype and allele frequencies of VDR-BsmI polymorphism in patients and controls

VDR-BsmI genotype distributions in patients and controls are presented in Table 1. VDR genotypes were similar in controls of both sexes (² = 0.27; 2 degrees of freedom; P = 0.87; data not shown). The genotype distribution for our controls was similar to that in a previous report of Japanese women who resided in the Tokyo metropolitan area (15).

VDR association with GD was analyzed with respect to sex, a factor that influences susceptibility to GD (Table 1). The distributions of genotype and allele frequencies differed between female GD patients and controls (² = 9.66; 2 degrees of freedom; P = 0.008 and ² = 8.74; 1 degree of freedom; P = 0.003, respectively), with the relative risk for the B phenotype of 1.7. Bb genotypes and B allele occurred more frequently in male patients than in controls, with the relative risk for the B phenotype of 1.2. The distributions of genotype and allele frequencies did not differ significantly between male GD patients and controls (² = 2.35; 2 degrees of freedom; P = 0.31 and ² = 0.63; 1 degree of freedom; P = 0.43, respectively).

Relation between 1,25-(OH)₂D₃ and BsmI genotype

The VDR B/b alleles have been linked to serum 1,25-(OH)₂D₃ levels in some studies (15, 26). To evaluate whether the associations are mainly from coupling of the B/b alleles to serum 1,25-(OH)₂D₃ levels, these levels were measured in the present study group of GD patients in remission (Fig. 1). No relation was detected between this polymorphism and serum 1,25-(OH)₂D₃ levels in the patients.

View larger version (19K): [in this window] [in a new window]   Figure 1. Analysis of GD patients in remission. Effects of the BsmI genotype on the serum concentration of 1,25-(OH)2D3.

To confirm an association between a cluster of polymorphisms in the 3'-end of the VDR gene (BsmI, ApaI, and TaqI) (15), we also examined the ApaI gene polymorphism in Japanese patients with GD. The ApaI polymorphism is linked to the BsmI polymorphism (75% linkage) (12.15). VDR-ApaI genotype distributions in patients and controls are presented in Table 2. VDR genotypes were similar in controls of both sexes (² = 0.40; 2 degrees of freedom; P = 0.82; data not shown). The genotype distribution for our controls was similar to that in a previous report of Japanese women who resided in the Tokyo metropolitan area (15).

VDR association with GD was analyzed with respect to sex (Table 2). The distributions of genotype and allele frequencies differed between female GD patients and controls (² = 8.36; 2 degrees of freedom; P = 0.015 and ² = 4.59; 1 degree of freedom; P = 0.032, respectively), with the relative risk for the A phenotype of 1.2. AA genotypes and A allele occurred more frequently in male patients than in controls, with the relative risk for the A phenotype of 1.2. The distributions of genotype and allele frequencies did not differ significantly between male GD patients and controls (² = 2.53; 2 degrees of freedom; P = 0.28 and ² = 1.94; 1 degree of freedom; P = 0.16, respectively).

Joint distribution of VDR-FokI and VDR-BsmI genotypes

We recently reported that the VDR-FokI polymorphism is associated with GD in Japanese women (11). The genotype distributions among the GD patients were 48% FF, 41% Ff, and 11% ff; distributions among control subjects were 33% FF, 55% Ff, and 12% ff. The distribution of genotype frequencies differs significantly between GD and controls (² = 5.99; 2 degrees of freedom; P = 0.0386) (11). Allele frequencies in the patients were 31% f and 69% F; in controls they were 39% f and 61% F. The distribution of allele frequencies also differed between GD patients and controls (² = 3.94; 1 degree of freedom; P = 0.0472) (11).

The joint distribution of the BsmI and FokI genotypes is shown in Table 3. The genotypes appeared to be independent of each other in both GD patients (² = 9.26; P = 0.06) and controls (² = 2.25; P = 0.69).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Recent studies describe the molecular basis of the immunomodulatory activity of 1,25-(OH)₂D₃, the active biological form of vitamin D (30, 31, 32). 1,25-(OH)₂D₃ inhibits T cell activation in vitro and in vivo and suppresses the production of interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor, and interferon- (30). These cytokines play important roles in the development of T helper 1 cells, which are believed to be involved in the pathogenesis of chronic inflammatory autoimmune diseases (31). Kawakami-Tani et al. (32) demonstrated a beneficial effect of treatment with 1,25-(OH)₂ D₃ on serum thyroid hormone concentrations in hyperthyroid patients with untreated GD, suggesting that 1,25-(OH)₂ D₃ could contribute to the treatment of hyperthyroidism in these patients.

Common allelic variants in the gene encoding VDR have been associated with differences in BMD (12, 15, 33, 34, 35). Morrison et al. (12, 33) detected a significant relation among a BsmI RFLP in the VDR gene, serum osteocalcin, and BMD in Australian women of English and Irish descent. The VDR B/b alleles have been linked to serum 1,25-(OH)₂D₃ levels in some studies (15, 26). In the present study we observed a relation between the BsmI polymorphism and serum 1,25-(OH)₂D₃ levels in the GD patients in remission (Fig. 1). However, there was no significant difference in these levels among the GD patients in remission.

Allelic frequencies for this and other VDR RFLPs (ApaI and TaqI) differ between Caucasian and Japanese women (15, 35). Genotypic analyses of RFLPs (BsmI, ApaI, and TaqI) showed the BBAAtt genotype to be relatively common (16.7%) in Caucasian populations and rare in the Japanese population (1.4%) (15). We detected only 3 BB homozygotes among 132 female Japanese patients (2.3%). We first investigated VDR-FokI genotype frequencies and found a statistically significant tendency toward overrepresentation of the FF genotype in patients (48%) compared with controls (33%), which suggests that the F allele may predispose an individual to GD (11). In the present study we found a statistically significant tendency toward overrepresentation of the Bb genotype in patients (34%) compared with controls (23%), suggesting that the B allele may predispose an individual to GD. These findings indicate that the two polymorphisms are both related to GD. Alternatively, as there appears to be no link between this polymorphism and the FokI polymorphism (18, 19, 20), the VDR polymorphisms may be linked to another nearby gene, and these associations may not be related to the VDR itself (18).

Several genes have been examined in the past as possible contributors to GD susceptibility, including HLA and CTLA-4 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10). Tomer et al. performed an entire genome linkage study on a dataset of 56 multiplex, multigenerational autoimmune thyroid disease (AITD) families (354 individuals) using 387 microsatellite markers (36). They identified 6 loci that showed evidence of linkage to AITD (36). One locus, on chromosome 6p (AITD-1), was linked with GD and Hashimoto’s thyroiditis (HT) [maximum logarithm of odds (LOD) score (MLS), 2.9] (36). This locus was near, but distinct from, the HLA region. One locus on chromosome 13q32 (HT-1) was linked to HT (MLS, 2.1), and another locus on chromosome 12q22 (HT-2) was linked to HT in a subgroup of the families (MLS, 3.8) (36). The latter locus was close to, but distinct from, the VDR region. Three loci showed evidence for linkage with GD: GD-1 on chromosome 14q31 (MLS, 2.5) (37), GD-2 on chromosome 20q11.2 (MLS, 3.5) (38), and GD-3 on chromosome Xq21 (MLS, 2.5) (39). There has been no further proof that any of the genes actually exist. Although Barbesino et al. did not find evidence of a link between the CTLA-4 gene and familial AITD, they obtained low positive LOD scores (1.0) for CTLA-4 at higher recombination fractions, suggesting that a gene in the region (not CTLA-4) may be involved in susceptibility to AITD (40). Indeed, another group found, for the first time, unequivocal evidence (P = 0.0004) for linkage of GD to the D2S117 region of 2q33 with a locus-specific sibling risk ratio (_s) of 2.2 (6). If other studies find higher LOD scores for VDR at higher recombination fractions in the future, then further studies on the VDR gene region and fine-mapping of the locus would be necessary to identify the genetic susceptibility in this region.

Recently, the existence of a VDR gene polymorphism has been proven, and its association to VDR-BsmI genotypes with osteoporosis (12, 15), pHPT (21, 22), IDDM (23), and MS (24) has been reported. Carling et al. described marked overrepresentation of the polymorphic VDR alleles b, a, and T in patients with pHPT, and they reported that low VDR messenger ribonucleic acid levels associated with the b, a, and T alleles may affect the calcitriol-mediated control of parathyroid function (21, 22). McDermott et al. suggested that a polymorphism within or close to the VDR gene may modify susceptibility to IDDM in subjects living in South India (23). Another group found an association of VDR gene polymorphism with MS in Japanese patients (24). In the present study the distributions of genotype and allele frequencies only differed significantly between female GD patients and controls. One possible reason for the association could be the female preponderance of GD patients. The role of VDR gene polymorphism should be studied further in other populations, and the distribution of other polymorphisms, such as the polyadenylase polymorphism further down the VDR 3'-untranslated region (16, 17), should also be analyzed with respect to susceptibility for GD. Our data show that in addition to the VDR-FokI gene region, the VDR-BsmI and ApaI gene regions are associated with GD.

In summary, we characterized BsmI and ApaI genotype frequencies in Japanese patients with GD and in control subjects, and we observed that the gene regions are associated with GD. We suggest that B and A alleles may predispose an individual to GD. The VDR gene or another nearby gene could indicate a non-HLA-linked susceptibility gene for GD, such as the CTLA-4 gene (6, 7, 8, 9, 10), and further study is warranted.

	Acknowledgments

 
We thank S. Mukae and S. Aoki for help with the recruitment of control subjects.

	Footnotes

 
¹ This work was supported in part by the High-Technology Research Center Project from the Ministry of Education, Science, Sports, and Culture of Japan. Part of this work was presented at the 12th International Thyroid Congress, Kyoto, Japan, 2000.

Received April 21, 2000.

Revised August 1, 2000.

Accepted August 23, 2000.

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