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.


METHODS
Retrospective analysis.


METHODS
The TH secretion in response to 500  μg 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) (FT(4); 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 FT(4) secretion with a normal T(3) 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.
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Maya Y
MY
Peltsverger
Peter W
PW
Butler
Anna Teresa
AT
Alberobello
Sheila
S
Smith
Yanina
Y
Guevara
Ornella M
OM
Dubaz
Javier A
JA
Luzon
Joyce
J
Linderman
Francesco S
FS
Celi
D000227:Adenine Nucleotides / Q000235:genetics; D000328:Adult; D015331:Cohort Studies; D005260:Female; D006150:Guanine Nucleotides / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics* / Q000502:physiology; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D012189:Retrospective Studies; D013972:Thyrotropin / Q000096:biosynthesis* / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000097:blood* / Q000378:metabolism; D055815:Young Adult; D000097564:Iodothyronine Deiodinase Type II
D000227:Adenine Nucleotides; D006150:Guanine Nucleotides; D007453:Iodide Peroxidase; D013972:Thyrotropin; D013973:Thyrotropin-Releasing Hormone; D000097564:Iodothyronine Deiodinase Type II