Vitamin D metabolism genes have been associated with type 1 diabetes (T1D) risk, but only recently have these genes been investigated in islet autoimmunity (IA), the pre-clinical phase of T1D. In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 22 single nucleotide polymorphisms (SNPs) in 8 vitamin D-related genes/regions (CYP24A1, CYP2R1, CYP27A1, CYP27B1, DHCR7, GC, VDR and C10orf88) were genotyped using the ImmunoChip, a custom genotyping array of 200K SNPs covering 186 regions associated with autoimmunity. Persistent IA was defined as positivity for GAD65A, IAA or IA-2A autoantibodies on 2 or more visits, and T1D was defined using ADA criteria. After removing SNPs in complete linkage disequilibrium, 15 SNPs were analyzed using time-to-event analysis. Analyses were restricted to non-Hispanic whites from US and European sites, with adjustment for HLA-DQ genotype, family history of T1D, country, sex and ancestry (using principal components). Analyses examining progression to T1D in IA positive children were also adjusted for age at first IA positivity. Of 5,812 children followed from birth to a median 4.9 years (range 0.5-8.8 years), 418 attained persistent IA positivity and, of these, 118 progressed to T1D. Three SNPs were associated with development of IA; rs2710246 (CYP24A1, HR: 0.84, 95%CI: 0.73-0.97, p=0.020), rs7041 (GC, HR: 1.23, 95%CI 1.07-1.40, p=0.0036), and rs11568820 (VDR-Cdx2, HR: 1.22, 95%CI: 1.04-1.44, p=0.016). Two additional SNPs in VDR were marginally associated with progression to T1D in IA positive children: rs1544410 (Bsm1, HR: 0.79, 95%CI: 0.60-1.05, p=0.097) and rs7975232 (Apa1, HR: 1.34, 95%CI: 1.005-1.79, p=0.046). These data support the role of vitamin D metabolism genes in the development of IA and progression to T1D in early childhood in children at increased risk for T1D.
Funded by NIH, NIDDK, NIAID, NICHD, NIEHS, JDRF and CDC.