Original article:
Vitamin D receptor allele combinations influence genetic susceptibility to Type 1 diabetes in Germans. Pani MA, Knapp M, Donner H et al. Diabetes 2000; 49: 504–7.

Summary
Pani et al. describe a correlation between certain vitamin D receptor (VDR) allele combinations and susceptibility to Type 1 diabetes in the German population, pointing towards a possible linkage between VDR or a nearby gene with susceptibility to the disease. This group studied the possible linkage of VDR polymorphisms by using the FokI, BsmI, ApaI and TaqI restriction endonucleases and found a significant transmission disequilibrium for several VDR haplotypes derived from the combined analysis of the BsmI/ApaI/TaqI sites. Some haplotypes showed a significantly enhanced transmission, while others had a reduced transmission.

Comment
This is one of many observations indicating a correlation between vitamin D metabolism and autoimmune diseases, Type 1 diabetes in particular. Correlations between VDR polymorphisms but also vitamin D binding protein (DBP) alleles and Type 1 diabetes have been described in different populations [1–4]. The meaning of these correlations between genetic markers of vitamin D metabolism and Type 1 diabetes is unclear. Although these data could still point towards the presence of a true IDDM gene in the vicinity of the VDR or DBP gene, thus falsely correlating vitamin D with Type 1 diabetes, the odds that this would be the case for VDR and DBP are very slim. A true correlation between vitamin D and Type 1 diabetes is more likely. Other arguments also point in this direction. A statistical correlation was observed in the epidemiological EURODIAB study by Dahlquist et al. between vitamin D supplements in early life and incidence of Type 1 diabetes, indicating that infants who received supplements of vitamin D in their first months of life had a lower incidence of Type 1 diabetes [5]. Very recently, a similar protective correlation was seen between the administration of cod liver oil (rich in vitamin D) to pregnant Norwegian women and Type 1 diabetes in their offspring [6]. This protective effect of vitamin D supplements can be attributed to effects on both the b-cell and on the immune system. Vitamin D, more particularly its activated form 1,25-dihydroxyvitamin D3, stimulates insulin synthesis and secretion and protects b-cells against destruction by inflammatory cytokines [7]. This effect of vitamin D on the b-cell should not be neglected and might be an explanation why correlations are observed not only between VDR/DBP polymorphisms and Type 1 diabetes but also Type 2 diabetes [8–11].
Another way in which vitamin D may act as a critical protective agent in Type 1 diabetes is by its immunomodulatory action. Immunomodulating properties, amongst which prevention of Type 1 diabetes in the non-obese diabetic (NOD) mouse, have been described for the activated form of vitamin D [12, 13], and abnormalities in the enzyme that activates vitamin D to 1,25-dihydroxyvitamin D3, 1a-hydroxylase, locally in activated macrophages have been described in NOD mice [14]. Arguments that primarily the immune pathway is important in the protective correlations are supported by the observation on VDR polymorphisms and protection against Graves’ disease in Japanese patients [15].
The exact meaning of the correlations between vitamin D metabolism and Type 1 diabetes remains unclear, but there is an overwhelming amount of evidence to suggest that something is indeed ‘out there’. These data do not implicate an immediate need for reconsideration of the present consensus on vitamin D supplements in early childhood, but should be considered as another stone in building our understanding of the intricate processes leading to Type 1 diabetes in humans. They might, however, lead to the design of primary prevention trials using dietary interventions such as vitamin D (or better 1,25-dihydroxyvitamin D) supplements, in genetically at-risk individuals. These trials will have to be large scale and it will take many years before the effects of the intervention can be evaluated. Small-scale individual initiatives should be avoided, considering the potential side effects on calcium metabolism of these substances. A major breakthrough on this point may come from the development of non-calcaemic structural analogues of the molecule which share the immunomodulatory- or b-cell-protective capacities but not the calcaemic effects with the parent compound.

References
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Summary and Comment:
Chantal Mathieu, Leuven, Belgium