Vitamin D 1α-hydroxylase (CYP1α) polymorphism in Graves' disease, Hashimoto's thyroiditis and type 1 diabetes mellitus

Objective: The vitamin D endocrine system plays a role in the regulation of (auto)immunity and cell proliferation. Vitamin D la-hydroxylase (CYP1alpha) 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 CYP1alpha polymorphism for an association with type I diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. Design and methods: Four hundred and seven Caucasian pedigrees with one offspring affected by either type I 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 CYP1alpha 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 chi(2) testing. Results: There was no deviation from the expected transmission frequency in either type I diabetes mellitus (P = 0.825), Graves' disease (P = 0.909) or Hashimoto's thyroiditis (P = 0.204). However, in Hashimoto's thyroiditis the CYP1alpha C allele was significantly more often transmitted to HLA-DQ2(-) patients (27 transmitted vs 14 not transmitted; TDT: P = 0.042) than expected. The C allele was less often transmitted to HLA-DQ2(+) patients (9 transmitted vs 12 not transmitted; TDT: P = 0.513), although the difference was not significant (chi(2) test: P = 0.143). A similar difference was observed in type I diabetes between offspring with high and low risk HLA-DQ haplotypes (chi(2) test: P = 0.095). Conclusions: The CYP1alpha 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 I diabetes and Hashimoto's thyroiditis should be further investigated as well as its functional implications.