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.
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.
Clinical Endocrinology Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1613, USA.
Peter W
PW
Butler
Sheila M
SM
Smith
Joyce D
JD
Linderman
Robert J
RJ
Brychta
Anna Teresa
AT
Alberobello
Ornella M
OM
Dubaz
Javier A
JA
Luzon
Monica C
MC
Skarulis
Craig S
CS
Cochran
Robert A
RA
Wesley
Frank
F
Pucino
Francesco Saverio
FS
Celi
D000328:Adult; D015331:Cohort Studies; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
D007453:Iodide Peroxidase; D013973:Thyrotropin-Releasing Hormone; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II