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

Context: Iodothyronine deiodinases D1, D2, and D3 play an important role in synthesis and degradation of T3. The relationship between serum TSH and free T4 (FT4) 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. Design: We collected 1905 serum FT4 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. Setting: The study was conducted at Leiden University Medical Center, a tertiary referral center for DTC. Patients: One hundred fifty-one consecutive patients were treated and cured for DTC. Main Outcome Measure: Slopes and intercepts of regression equations representing the relationship between InTSH and FT4 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)]/[FT4(pmol/liter)]), the intercept, 4.95. For heterozygous patients, the slope was −0.30 ± 0.028 (ln[TSH(mU/liter)]/[FT4(pmol/liter)]), the intercept, 4.23. The slope of the homozygous patients was −0.35 ± 0.026 (ln[TSH(mU/liter)]/[FT4(pmol/liter)]) and the intercept, 6.07 (P = 0.036 compared with wild-type and heterozygous patients). Conclusion: Our data suggest that the negative feedback of FT4 on TSH is weaker in patients homozygous for the D2-rs12885300 T allele than in wild-type and heterozygous subjects.