The Thr92Ala 5' type 2 deiodinase gene polymorphism is associated with a delayed triiodothyronine secretion in response to the thyrotropin-releasing hormone-stimulation test: a pharmacogenomic study

Abstract

Background: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland.

Methods: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes.

Results: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups.

Conclusions: The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis.

Trial registration: ClinicalTrials.gov NCT00812149.

Figures

FIG. 1.

CONSORT chart describing subject recruitment and testing.

FIG. 2.

Mean change in serum thyroid hormone and thyrotropin levels after the intravenous injection of 500 μg of thyrotropin-releasing hormone (TRH), by Thr92Ala deiodinase type 2 genotype. Serum levels were measured at −15, 0, 5, 10, 15, 20, 30, 60, 120, and 180 minutes of TRH injection. Error bars represent the standard error of the mean at each time point. *p = 0.029 Thr/Thr versus Ala/Ala.

FIG. 3.

Time to 50% of maximum rise in serum total triiodothyronine (TT3) levels after the injection of 500 μg of TRH by Thr92Ala deiodinase type 2 genotype. These values were derived from a nonlinear (second order polynomial) regression analysis of the primary data. Horizontal bars represent the group mean ± standard error.

FIG. 4.

Mean serum prolactin concentration after the injection of 500 μg of TRH by Thr92Ala deiodinase type 2 genotype. No significant differences were observed at any time point among genotypes. Error bars represent the standard error of the mean at each time point.