Giulia Brigante1, Giorgia Spaggiari1, Daniele Santi1, Katia Cioni1, Valentina Gnarini1, Chiara Diazzi1, Elisa Pignatti2, Livio Casarini2, Marco Marino2, Frank Tüttelmann3, Cesare Carani1, Manuela Simoni4. 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.
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.
Authors: Robin P Peeters; Hans van Toor; Willem Klootwijk; Yolanda B de Rijke; George G J M Kuiper; Andre G Uitterlinden; Theo J Visser Journal: J Clin Endocrinol Metab Date: 2003-06 Impact factor: 5.958
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