We found an association between the VDR-FokI polymorphism and T1DM in our study population. Selective β-cell destruction, which is observed in T1DM, is thought to be caused by a T-cell-mediated autoimmune process . Genetic susceptibility to T1DM is well established, and certain HLA pheno- and genotypes are associated with T1DM; for example, HLA-DR 3 and -DR 4 in Caucasian populations , and HLA-DR 4 and -DR 9 in Japanese populations . Recent genome-wide searches and several candidate gene studies have revealed new regions possibly associated with T1DM [8,9,10,11,12,13,14,15,16,45,46].
Vitamin D hormone has important immunomodulatory properties and influences insulin secretion . This hormone inhibits T-cell activation both in vitro and in vivo and the secretion of IL-1, IL-2, IL-6, IL-12, TNF, and interferon (IFN)-γ [48,49,50,51]. These cytokines play important roles in the development of T cells, which are believed to be involved in the pathogenesis of several chronic inflammatory autoimmune diseases . In recent studies, 1,25-dihydroxyvitamin D3 was shown to inhibit IL-12 production by macrophages and dendritic cells by suppressing transcriptional activation of the p35 and p45 genes, which code for subunits of IL-12. Transcriptional repression of the p40 gene is dependent on expression of VDR . In murine models, vitamin D administration prevents development of T1DM as well as the associated autoimmune insulitis . In Bangladeshi subjects, vitamin D levels were found to be reduced in those subjects most at risk for type 2 diabetes .
The VDR locus has been studied extensively for association with susceptibility to osteoporosis [23,24,25], primary hyperparathyroidism [26,27], and autoimmune diseases such as Graves' disease [28,29], Hashimoto's thyroiditis , and multiple sclerosis . The BsmI B allele of VDR has been associated with reduced bone mineral density in some studies [23,56], but not in others [57,58], and at least one study showed the b allele of VDR to be associated with particular subtypes of osteoporosis . The bb genotype has been associated with primary hyperparathyroidism in Swedish patients [26,27] and multiple sclerosis in Japanese patients . The FokI FF genotype for VDR has been associated with both Graves' disease  and Hashimoto's thyroiditis  in Japanese patients.
The role of the VDR gene in T1DM has also been examined [17,32]. Evidence for preferential transmission of the VDR b allele to affected offspring has been found in Indian Asians . Pani et al.  detected significant haplotype-wise extended transmission disequilibrium for the BsmI/ApaI/TaqI, BsmI/TaqI, and ApaI/TaqI haplotypes in Germans; analysis of the FokI site did not provide additional information on susceptibility. Recently, Chang et al. confirmed the association of these markers with T1DM in the Taiwanese population . Allelic frequencies for this and other VDR RFLPs (ApaI, TaqI) differ between Caucasian and Japanese subjects [24,60]. RFLP analysis of VDR revealed that the BBAAtt genotype is relatively common (16.7%) in Caucasian populations and rare in Japanese populations (1.4%) . Therefore, we investigated VDR-FokI polymorphism in this study. Our investigation of VDR-FokI genotype frequencies in Japanese subjects revealed that the FF genotype is significantly more common in T1DM patients (47%) than in control subjects (33%), suggesting that patients with this genotype may be predisposed to T1DM .
In contrast to our findings for T1DM, an increased frequency of the F allele, because it encodes a VDR isoform with higher transcriptional activity, has a beneficial effects in the prevention of osteoporosis, and should lead to higher immunomodulatory activity of the vitamin D hormone . Recently, Colin et al.  demonstrated in peripheral blood mononuclear cells with a natural VDR genotype a direct functional consequence of the VDR-FokI polymorphism for the action of 1,25-dihydroxyvitamin D3. They found that the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nM per f allele copy (P = 0.0036), while for BsmI genotypes no differences in ED50 were observed . The apparent discrepancy could be due to the effect of the genetic susceptibility to T1DM and ethnic differences related to VDR-FokI allelic prevalences as well as to environmental and geographic variations in calcium intake, exposure to sunshine, or other factors.
In the present study, the FF genotype (or presence of the F allele) of the VDR-FokI polymorphism was also associated with GAD65-Ab-positive T1DM in the Japanese population, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies. McDermott et al.  found no relation between the VDR-BsmI, -TaqI, or -ApaI polymorphism and GAD65 Ab status in Indian Asians. Thus, since there is apparently no linkage disequilibrium between FokI polymorphism and BsmI, ApaI, and TaqI polymorphisms [34,35,36,37], the VDR-FokI polymorphism seems to contribute to immunological heterogeneity of T1DM, although the mechanism remains unclear. Although no in vitro or animal studies have shown that VDR function is directly associated with antibody production in autoimmune disease or that this polymorphism might alter immune function, GAD65-Ab-negative diabetes patients could be subject to a different disease process or a different path of clinical development with regards to a possible VDR contribution. Both possibilities warrant further study.