Plasma 25-Hydroxyvitamin D Concentration and Risk of Islet Autoimmunity

Abstract

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 8,676 children at increased genetic risk of type 1 diabetes at six sites in the U.S. and Europe. We defined IA as positivity for at least one autoantibody (GADA, IAA, or IA-2A) on two or more visits. We conducted a risk set sampled nested case-control study of 376 IA case subjects and up to 3 control subjects per case subject. 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 = 0.93 for a 5 nmol/L difference; 95% 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 (1.00; 0.93, 1.07), 1 (0.92; 0.89, 0.96), and 2 (0.86; 0.80, 0.92). Vitamin D and VDR may have a combined role in IA development in children at increased genetic risk for type 1 diabetes.

Figure 1

ORs and 95% CIs for decreased risk of IA associated with 25(OH)D concentration (5 nmol/L increase) and being vitamin D sufficient (≥50 nmol/L) versus insufficient by number of minor alleles (the C allele) at rs7975232 in the vitamin D receptor gene. Analyses are adjusted for HLA-DR3/4 and the first two PCs indicating ancestry; and ORs are calculated from the SNP × vitamin D measure interaction terms. For childhood vitamin D measures, we analyzed 376 case subjects and their control subjects (297 case subjects with 3 control subjects, 71 case subjects with 2 control subjects, and 8 case subjects with 1 control subject) with complete plasma 25(OH)D and vitamin D genetic data. For the early infancy vitamin D measures, we analyzed 360 case subjects and their control subjects (269 case subjects with 3 control subjects, 83 case subjects with 2 control subjects, and 8 case subjects with 1 control subject).