title: The type 2 deiodinase ORFa-Gly3Asp polymorphism (rs12885300) influences the set point of the hypothalamus-pituitary-thyroid axis in patients treated for differentiated thyroid carcinoma.
abstract: BACKGROUND
  Iodothyronine deiodinases D1, D2, and D3 play an important role in synthesis and degradation of T(3). The relationship between serum TSH and free T(4) (FT(4)) levels is determined by an individual set point of the hypothalamus-pituitary-thyroid axis.
  
  
  OBJECTIVE
  Several polymorphisms have been described in D1 and D2 of which some are associated with serum TSH and iodothyronine levels. In this study we investigate whether polymorphisms of D1 and D2 influence the set point of the hypothalamus-pituitary-thyroid axis.
  
  
  METHODS
  We collected 1905 serum FT(4) and TSH measurements during 11.5 ± 8.8 yr of follow-up in patients treated for differentiated thyroid carcinoma (DTC). We determined these polymorphisms: D1-rs11206244, D1-rs12095080, D2-rs225014, and D2-rs12885300. Effects of these polymorphisms on the set points of the hypothalamus-pituitary-thyroid axis were analyzed with a linear mixed model.
  
  
  METHODS
  The study was conducted at Leiden University Medical Center, a tertiary referral center for DTC.
  
  
  METHODS
  One hundred fifty-one consecutive patients were treated and cured for DTC.
  
  
  METHODS
  Slopes and intercepts of regression equations representing the relationship between InTSH and FT(4) were measured for all polymorphisms.
  
  
  RESULTS
  DTC patients homozygous for the D2-rs12885300 T allele have an altered set point of the hypothalamus-pituitary-thyroid axis. The slope of the regression line (corrected for age, body mass index, and gender) for wild-type patients was -0.32 ± 0.028 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]), the intercept, 4.95. For heterozygous patients, the slope was -0.30 ± 0.028 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]), the intercept, 4.23. The slope of the homozygous patients was -0.35 ± 0.026 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]) and the intercept, 6.07 (P = 0.036 compared with wild-type and heterozygous patients).
  
  
  CONCLUSIONS
  Our data suggest that the negative feedback of FT(4) on TSH is weaker in patients homozygous for the D2-rs12885300 T allele than in wild-type and heterozygous subjects.
authors.affiliation: Department of Endocrinology and Metabolism, Leiden University Medical Center, 2300 RC Leiden, TheNetherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Hoftijzer
authors.forename: K A
authors.initials: KA
authors.lastname: Heemstra
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
authors.forename: S
authors.initials: S
authors.lastname: le Cessie
authors.forename: R P
authors.initials: RP
authors.lastname: Peeters
authors.forename: E P M
authors.initials: EP
authors.lastname: Corssmit
authors.forename: J W A
authors.initials: JW
authors.lastname: Smit
mesh_terms: D000328:Adult; D000483:Alleles; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D005260:Female; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D013972:Thyrotropin / Q000097:blood; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D013972:Thyrotropin; D000097564:Iodothyronine Deiodinase Type II