1,25-dihydroxyvitamin D3[1,25(OH)2D3] not only regulates calcium metabolism but also modulates the immune system. Some reports have suggested that 1,25(OH)2D3 helps to prevent the development of type 1 diabetes. The association between the vitamin D receptor (VDR) genotype and susceptibility to type 1 diabetes has been examined, but a definitive conclusion has not yet been reached (1,2). We examined the VDR genotype in juvenile Japanese patients with type 1 diabetes.
A total of 108 diabetic patients (41 boys and 67 girls, age of onset 0.4–18 years with a median age of 8.9) and 120 nonrelated nondiabetic subjects were studied. Three polymorphic restriction fragment-length polymorphisms (RFLPs), i.e., Fok I, ApaI, and TaqI, were genotyped by PCR-RFLP method. The genotype or allele frequencies were compared statistically by the χ2 test. The significance of differences in each genotype for the age of onset was tested with the Mann-Whitney U test.
Among the patients, the FF (n = 50) and tt (n = 5) genotypes were found relatively frequently, and aa (n = 46) was infrequent compared with those in control subjects, but these differences were not statistically significant (P = 0.14, 0.18, and 0.38 for FF, tt, and aa genotypes, respectively). There was also no significant difference in the allele frequency of each polymorphism, although the incidence of the F allele tended to be higher in the diabetic patients (P = 0.051). Concerning the age of onset of diabetes, patients with the ff genotype (n = 12, median 5.2 years, range 1.7–11.0) were significantly younger at onset than those with FF (n = 50, 9.7 years, 0.4–15.9, P = 0.01) or Ff (n = 46, 8.9 years, 0.9–18.0, P = 0.03). No significant association was observed between the TaqI or ApaI genotype and the age of onset.
The ff genotype has been reported to be associated with a lower expression of VDR mRNA and reduced inhibition of phytohemagglutinin-stimulated growth of peripheral blood mononuclear cells. Thus, the Fok I genotype may influence the rate of the progression of insulitis by modifying the autoimmune process, which may have led to the significant difference in the age of onset. The relatively high frequency of the F allele in diabetic patients, which has also been found in Japanese adult diabetic patients (2), is apparently inconsistent with this observation. A possible explanation is that the impact of Fok I polymorphism may not be strong enough to prevent the progression of autoimmune insulitis into overt diabetes and thus does not influence susceptibility to the disease itself.
In conclusion, VDR gene polymorphism does not appear to have a strong enough impact to clearly influence susceptibility to the disease itself, but Fok I polymorphism might influence the age of onset of diabetes in juvenile Japanese diabetic patients.
Address correspondence to Ichiro Yokota, Department of Pediatrics, Tokushima University School of Medicine, Kuramoto-cho 3, Tokushima 770-8503, Japan. E-mail: firstname.lastname@example.org.