Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Islet Autoimmunity and Progression to Type 1 Diabetes: The Diabetes Autoimmunity Study in the Young (DAISY)

Context: Vitamin D metabolism genes have been associated with type1diabetes (T1D) risk; however, these genes have not been investigated for association with the preclinical phase of T1D, islet autoimmunity (IA). Studies of vitamin D metabolism genes may elucidate the role of vitamin D in complex diseases. Objective: The objective of the study was to explore the association between seven vitamin D metabolism gene single-nucleotide polymorphisms (SNPs) and the risk of IA and progression to T1D. Setting: Newborn screening for human leukocyte antigen, sibling and offspring recruitment, and follow-up took place in Denver, Colorado. Participants: A total of 1708 children at increased genetic risk of T1D participated in the study: 148 developed IA and 62 IA-positive children progressed to T1D. Main Outcome Measures: IA, defined as positivity for glutamic acid decarboxylase, insulin, or IA-2 autoantibodies on two or more consecutive visits, and T1D, diagnosed by a physician, were the main outcome measures. Results: The risk of IA was associated with DHCR7/ NADSYN1 rs12785878 and CYP27B1 rs4646536 [ hazard ratio 1.36,95% confidence interval 1.08-1.73 (for each additional minor allele) and hazard ratio 0.59, 95% confidence interval 0.39-0.89 (for A/ G compared with the A/ A genotype), respectively]. None of the vitamin D SNPs typed was associated with progression to T1D in IA-positive children. Six of the seven SNPs were significantly associated with 25-hydroxyvitamin D levels. Conclusions: DHCR7/ NADSYN1 rs12785878 and CYP27B1 rs4646536 may play an important role in islet autoimmunity, the preclinical phase of T1D. These findings should be replicated in larger cohorts for confirmation.