Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity

We examined the association between plasma 25-hydroxyvitamin D (25[OH]D) concentration and islet autoimmunity(IA); and whether vitamin D gene polymorphisms modify the effect of 25(OH)D on IA risk. We followed 8676 children at increased genetic risk of type 1 diabetes(T1D) at 6 sites in the US and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA or IA-2A) on 2 or more visits. We conducted a risk-set sampled nested case-control study of 376 IA cases and up to 3 controls per case. 25(OH)D concentration was measured on all samples prior to, and including the first IA positive visit. Nine polymorphisms in VDR, CYP24A, CYP27B1, GC, and RXRA were analyzed as effect modifiers of 25(OH)D. Adjusting for HLA-DR-DQ and ancestry, higher childhood 25(OH)D was associated with lower IA risk (odds ratio(OR): 0.93 for a 5 nmol/L difference; 95% confidence interval(CI): 0.89,0.97). Moreover, this association was modified by VDR rs7975232 (interaction p=0.0072), where increased childhood 25(OH)D was associated with a decreasing IA risk based upon number of minor alleles: 0 (OR:1.00; CI:0.93,1.07), 1 (OR:0.92; CI:0.89,0.96), and 2 (OR:0.86; CI:0.80,0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for T1D.