The -258A/G (SNP rs12885300) polymorphism of the human type 2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH.

Objective: Type 2 deiodinase gene (DIO2) polymorphisms have been associated with changes in pituitary-thyroid axis homeostasis. The -258A/G (SNP rs12885300) polymorphism has been associated with increased enzymatic activity, but data are conflicting. To characterize the effects of -258A/G polymorphism on intrathyroidal thyroxine (T-4) to triiodothyronine (T-3) conversion and thyroid hormone (TH) secretion pattern, we studied the effects of acute, TRH-mediated, TSH stimulation of the thyroid gland. Design: Retrospective analysis. Methods: The TH secretion in response to 500 mu g i.v. TRH injection was studied in 45 healthy volunteers. Results: Twenty-six subjects (16 females and ten males, 32.8 +/- 10.4 years) were homozygous for the ancestral (-258A/A) allele and 19 (11 females and eight males, 31.1 +/- 10.9 years) were carriers of the (-258G/x) variant. While no differences in the peak TSH and T-3 levels were observed, carriers of the -258G/x allele showed a blunted rise in free T-4 (FT4; P < 0.01). The -258G/x92Thr/Thr haplotype, compared with the other groups, had lower TSH values at 60 min (P < 0.03). No differences were observed between genotypes in baseline TH levels. Conclusions: The -258G/x DIO2 polymorphism variant is associated with a decreased rate of acute TSH-stimulated FT4 secretion with a normal T3 release from the thyroid gland consistent with a shift in the reaction equilibrium toward the product. These data indicate that the -258G DIO2 polymorphism causes changes in the pattern of hormone secretion. These findings are a proof of concept that common polymorphisms in DIO2 can subtly affect the circulating levels of TH and might modulate the TH homeostasis.