OBJECTIVEVitamin D deficiency (25-hydroxyvitamin D [25(OH)D] <50 nmol/L) is commonly reported in both children and adults worldwide, and growing evidence indicates that vitamin D deficiency is associated with many extraskeletal chronic disorders, including the autoimmune diseases type 1 diabetes and multiple sclerosis.RESEARCH DESIGN AND METHODSWe measured 25(OH)D concentrations in 720 case and 2,610 control plasma samples and genotyped single nucleotide polymorphisms from seven vitamin D metabolism genes in 8,517 case, 10,438 control, and 1,933 family samples. We tested genetic variants influencing 25(OH)D metabolism for an association with both circulating 25(OH)D concentrations and disease status.RESULTSType 1 diabetic patients have lower circulating levels of 25(OH)D than similarly aged subjects from the British population. Only 4.3 and 18.6% of type 1 diabetic patients reached optimal levels (≥75 nmol/L) of 25(OH)D for bone health in the winter and summer, respectively. We replicated the associations of four vitamin D metabolism genes (GC, DHCR7, CYP2R1, and CYP24A1) with 25(OH)D in control subjects. In addition to the previously reported association between type 1 diabetes and CYP27B1 (P = 1.4 × 10−4), we obtained consistent evidence of type 1 diabetes being associated with DHCR7 (P = 1.2 × 10−3) and CYP2R1 (P = 3.0 × 10−3).CONCLUSIONSCirculating levels of 25(OH)D in children and adolescents with type 1 diabetes vary seasonally and are under the same genetic control as in the general population but are much lower. Three key 25(OH)D metabolism genes show consistent evidence of association with type 1 diabetes risk, indicating a genetic etiological role for vitamin D deficiency in type 1 diabetes.

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1a,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) has important effects on the growth and function of multiple cell types. These pleiotropic effects of 1,25(OH) 2 D 3 are mediated through binding to the vitamin D receptor (VDR). Several polymorphisms of the human VDR gene have been identified, with the FokI polymorphism resulting in VDR proteins with different structures, a long f-VDR or a shorter F-VDR. The aim of this study was to investigate the functional consequences of the FokI polymorphism in immune cells. In transfection experiments, the presence of the shorter F-VDR resulted in higher NF-jBand NFAT-driven transcription as well as higher IL-12p40 promoter-driven transcription. Marginal differences were observed for AP-1-driven transcription, and no differential effects were observed for transactivation of a classical vitamin D-responsive element. Concordantly, in human monocytes and dendritic cells with a homozygous short FF VDR genotype, expression of IL-12 (mRNA and protein) was higher than in cells with a long ff VDR genotype. Additionally, lymphocytes with a short FF VDR genotype proliferated more strongly in response to phytohemagglutinin. Together, these data provide the first evidence that the VDR FokI polymorphism affects immune cell behavior, with a more active immune system for the short F-VDR, thus possibly playing a role in immune-mediated diseases.

Thus, our findings reveal a novel association of CYP2R1 polymorphisms in patients with type 1 diabetes and with their circulating levels of 25(OH)D3.

OBJECTIVE-Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1␣,25-dihydroxyvitamin D (1␣,25(OH) 2 D) could protect from immune destruction of the pancreatic ␤-cells. 1␣,25(OH) 2 D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1␣-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes.RESEARCH DESIGN AND METHODS-We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms Ϫ1260CϾA (rs10877012) and ϩ2838TϾC (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene.RESULTS-We found evidence of association with type 1 diabetes for CYP27B1 Ϫ1260 and ϩ2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 Ϫ1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P ϭ 9.6 ϫ 10 Ϫ4 ) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P ϭ 3.9 ϫ 10 Ϫ3 ). The combined P value for an association with type 1 diabetes was 3.8 ϫ 10Ϫ6 . For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P ϭ 0.23). T ype 1 diabetes is strongly inherited and yet exhibits striking epidemiological features such as seasonality in diagnosis, with more cases diagnosed in the autumn and winter months, and a north-south geographical gradient, suggesting inverse correlation between the amount of sunshine and type 1 diabetes incidence (1,2). Lower serum concentrations of 1␣,25-dihydroxyvitamin D (1␣,25(OH) 2 D), the hormonally active form of vitamin D, and of its precursor 25-hydroxyvitamin D (25(OH)D) have been reported at the diagnosis of type 1 diabetes compared with normal control subjects (3-5). Epidemiological studies indicate that vitamin D supplementation in early childhood is associated with decreased type 1 diabetes incidence (6 -8). However, a direct role of impaired vitamin D metabolism in the etiology of type 1 diabetes has not been proven. If vitamin D is a significant factor in type 1 diabetes, then it might be expected that common functional sequence polymorphisms in the genes that influence vitamin D action could predispose to the disease. We have previously studied the gene of the vitamin D receptor (VDR), which binds 1␣,25(OH) 2 D and mediates the effects of vitamin D. We found no association between VDR sequence variants and type 1 diabetes, in contrast to some other studies with smaller sample sizes (9), and a recently conducted metaanalysis also found no evidence of association (10). CONCLUSIONS-TheSeveral studies have reported associations of type 1 diabetes and other autoimmune diseases with polymorphisms in the CYP27B1 gene on chromosome 12q13.1-q13.3 (11-14), which e...