The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

Giulia Brigante; Giorgia Spaggiari; Daniele Santi; Katia Cioni; Valentina Gnarini; Chiara Diazzi; Elisa Pignatti; Livio Casarini; Marco Marino; Frank Tüttelmann; Cesare Carani; Manuela Simoni

doi:10.1159/000358590

The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

Eur Thyroid J. 2014 Jun;3(2):101-8. doi: 10.1159/000358590. Epub 2014 Jun 7.

Affiliations

¹ Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
² Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Center of Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.
³ Institute of Human Genetics, University of Munster, Munster, Germany.
⁴ Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Center of Genomic Research, University of Modena and Reggio Emilia, Modena, Italy ; Azienda USL, Modena, Italy.

Abstract

Background: Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated.

Objectives: We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback.

Methods: We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT4 resulting in TSH levels detectable but <0.5 μIU/ml. The two SNPs rs3134105 and rs3110040 were identified as informative markers of the TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls.

Results: The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT4)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT3) and fT4, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT3/TSH (p = 0.01) and fT4/TSH ratios (p < 0.01).

Conclusions: We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT4 therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT4.

Keywords: Hypothalamo-pituitary sensitivity; TRHR; TSH suppression.