No abstract

Objective: The vitamin D endocrine system plays a role in the regulation of (auto)immunity and cell proliferation. Vitamin D 1a-hydroxylase (CYP1a) is one of the key enzymes regulating both systemic and tissue levels of 1,25-dihyroxyvitamin D 3 (1,25(OH) 2 D 3 ). Administration of 1,25(OH) 2 D 3 , whose serum levels were found to be reduced in type 1 diabetes and thyroid autoimmunity, prevents these diseases in animal models. We therefore investigated a recently reported CYP1a polymorphism for an association with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. Design and methods: Four hundred and seven Caucasian pedigrees with one offspring affected by either type 1 diabetes (209 families), Graves' disease (92 families) or Hashimoto's thyroiditis (106 families) were genotyped for a C/T polymorphism in intron 6 of the CYP1a gene on chromosome 12q13.1 -13.3 and transmission disequilibrium testing (TDT) was performed. Subsets of affected offspring stratified for HLA-DQ haplotype were compared using x 2 testing. Results: There was no deviation from the expected transmission frequency in either type 1 diabetes mellitus ðP ¼ 0:825Þ; Graves' disease ðP ¼ 0:909Þ or Hashimoto's thyroiditis ðP ¼ 0:204Þ: However, in Hashimoto's thyroiditis the CYP1a C allele was significantly more often transmitted to HLA-DQ2 2 patients (27 transmitted vs 14 not transmitted; TDT: P ¼ 0:042) than expected. The C allele was less often transmitted to HLA-DQ2 + patients (9 transmitted vs 12 not transmitted; TDT: P ¼ 0:513), although the difference was not significant (x 2 test: P ¼ 0:143). A similar difference was observed in type 1 diabetes between offspring with high and low risk HLA-DQ haplotypes (x 2 test: P ¼ 0:095). Conclusions: The CYP1a intron 6 polymorphism appears not to be associated with type 1 diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. A potential association in subsets of patients with type 1 diabetes and Hashimoto's thyroiditis should be further investigated as well as its functional implications.

Graves' disease and Hashimoto's thyroiditis are common autoimmune thyroid disorders. Experimentally, 1,25(OH)(2) D(3) prevents Hashimoto's thyroiditis. Vitamin D serum levels in Graves' disease were found to be significantly lower than in nonautoimmune hyperthyroidism. The polymorphic vitamin D-binding protein (DBP) greatly facilitates vitamin D actions, and DBP alleles differ regarding their affinity for 1,25(OH)(2) D(3). Therefore, we investigated polymorphisms of the DBP gene for an association with thyroid autoimmunity. Families with an offspring affected by Graves' disease (95 pedigrees) or by Hashimoto's thyroiditis (92 pedigrees) encompassing 561 individuals of Caucasian origin were genotyped for three DBP polymorphisms [(TAAA)(N) in intron 8; StyI; and HaeIII in exon 11]. Indirect haplotyping and (extended) transmission disequilibrium testing were performed. There was a significant transmission disequilibrium of the intron 8 polymorphism in patients with Graves' disease (P < 0.03) but not of the exon 11 polymorphism. In contrast, neither the intron 8 nor the exon 11 polymorphism was associated with Hashimoto's thyroiditis. Maternal and paternal transmission as well as allele frequencies in DQ2(+) and DQ2(-) patients did not differ in either disease. Therefore, allelic variants of the DBP gene confer susceptibility to Graves' disease but not to Hashimoto's thyroiditis in our population. These findings support a role of the vitamin D endocrine system in thyroid autoimmunity.