Vitamin D supplementation could possibly reduce the risk of type 1 diabetes in susceptible children.
Type 1 diabetes mellitus (TIDM) has been found to be more frequent in people who live at higher altitudes. These people are also at higher risk of developing a vitamin D deficiency. Since vitamin D is related to immune system regulation and increased autoimmunity, it is a potential contender in T1DM prevention. It has been suggested that vitamin D may be related to lower risk of T1DM in infants. Some studies have failed to find a relation between childhood dietary vitamin D and islet autoimmunity (IA). However, dietary intake of vitamin D is only one of the sources that depicts serum levels of 25-hydroxyvitamin D (25(OH)D). 25(OH)D is the precursor of vitamin D, and a good indicator of vitamin D levels in the body. Numerous other studies have found mixed results on whether 25(OH)D is associated with IA and T1DM. This is perhaps due to study design issues, population diversity, and/or failing to consider genetic variation.
Genes vital to the vitamin D pathway include, GC, CYP27B1, CYP24A1, VDR and RXRA. GC transports 25(OH)D and 1,25(OH)2D. CYP27B1 transforms 25(OH)D to 1,25(OH)2D. CYP24A1 is responsible for degradation of 1,25(OH)2D. VDR and RXRA both enable 1,25(OH)2D. Genetic variations of these genes may result in ineffective or insufficient levels of 25(OH)D and past studies have failed to consider this. Therefore, the main goal of the following prospective study, called The Environmental Determinants of Diabetes in the Young (TEDDY), was to evaluate 25(OH)D blood levels in early infancy and throughout childhood to determine how they affect IA risk. The study also aimed to identify whether gene variations in the vitamin D pathway alter the effect of 25(OH)D on IA.
The TEDDY study evaluated 8,676 children genetically susceptible to TIDM from 6 total centers in the U.S. and Europe. Children were screened as newborns and eligible for the study if they had T1DM associated HLA genotypes. Follow-up visits were conducted at 3 month intervals up to 48 months of age followed by 6 month intervals.
Autoantibodies to glutamate decarboxylase (GADA), insulinoma antigen-2 (IA-2A), and insulin (IAA) were measured along with 25(OH)D levels from collected blood samples. Children were considered IA positive if they had autoantibodies to the same antigen at two or more consecutive visits. A total of 376 children developed IA and 1,041 children who did not develop IA were used as controls in a nested case-control study. 25(OH)D levels were then compared between the positive cases and controls. Nine polymorphisms related to autoimmune disease were evaluated in the GC, CYP27B1, CYP24A1, VDR, and RXRA genes.
According to results, higher 25(OH)D levels in early infancy and childhood were related to lower IA risk. Vitamin D sufficiency (≥50 nmol/L) in early infancy resulted in a 40% IA risk reduction compared to infants who were insufficient. Vitamin D sufficiency (≥50 nmol/L) in childhood resulted in a 31% lower IA risk compared to children who were insufficient. A significant interaction was found between the VDR polymorphism rs7975232 and early infancy and childhood 25(OH)D levels (interaction p-value:0.0072, 0.0019). There was also a significant interaction found between the VDR polymorphism rs7975232 and early infancy and childhood vitamin D sufficiency (interaction p-value: 0.01, 0.0051). Higher 25(OH)D levels in both early infancy and childhood were related to a greater IA risk reduction for every additional minor allele. However, this relation was not seen in infants and children with no minor alleles. In children with 2 minor alleles and sufficient vitamin D, 59% had a lower risk of IA compared to insufficient children. In infants with 2 minor alleles and sufficient vitamin D, 67% had a lower risk of IA compared to insufficient infants.
This study suggests that among infants and children who have the VDR gene polymorphism, higher vitamin D levels are associated with greater IA risk reduction. This however, did not hold true for those lacking the VDR variant gene. Although the study had enough power to identify this relation between 25(OH)D and VDR, there may be less significant genetic interactions that might have been missed. The study was not able to evaluate the relation between IA and vitamin D deficiency because there were only 6% of children in the case-control study that had a deficiency (<30 nmol/L). The study was also not able to prove cause and effect on how VDR polymorphisms affect 25(OH)D concentration.
- In infants and children at increased risk of type 1 diabetes, higher vitamin D levels may decrease risk of IA development.
- Upon further analysis, only infants and children with presence of VDR variant genes showed IA risk reduction with higher vitamin D levels.
- Identifying vitamin D status and VDR variants along with other genetic variants in the vitamin D pathway, may help determine who will most likely benefit from therapy.
Norris JM, Lee HS, Frederiksen B, et al. Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity. Diabetes. 2017; 66(11): 1-35.
Graciela Nieto, Pharm. D. Candidate 2018, LECOM School of Pharmacy