title: The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Brigante
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Spaggiari
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Santi
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Cioni
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gnarini
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Diazzi
authors.affiliation: 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.
authors.forename: Elisa
authors.initials: E
authors.lastname: Pignatti
authors.affiliation: 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.
authors.forename: Livio
authors.initials: L
authors.lastname: Casarini
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Marino
authors.affiliation: Institute of Human Genetics, University of Munster, Munster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tüttelmann
authors.affiliation: Unit of Endocrinology and Metabolism, Department of Biomedical, Metabolic and Neural Sciences, Modena, Italy ; Azienda USL, Modena, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Carani
authors.affiliation: 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.
authors.forename: Manuela
authors.initials: M
authors.lastname: Simoni
keywords: Hypothalamo-pituitary sensitivity; TRHR; TSH suppression
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