The TRHR gene is associated to hypothalamo-pituitary sensitivity to levothyroxine in thyroidectomized patients

Background: Patients thyroidectomized for thyroid cancer need variable doses of levothyroxine (LT4) to obtain TSH suppression. A predetermined thyroid function set-point for each individual has been hypothesized, suggesting a genetic influence in the regulation of pituitary-thyroid axis. We hypothesized of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to the negative feedback of the thyroid hormones. Methods: We performed a case–control association study, enrolling 107 thyroidectomized patients, in follow-up for differentiated thyroid cancer, and 99 volunteer controls. Patients were evaluated first when TSH levels were suppressed (<0.1 mIU/l), by the lowest effective LT4 dose, and then when TSH was subsuppressed (0.1<TSH<0.5 mIU/l). We selected two SNPs of TRHR gene, rs3134105 and rs3110040, identified as informative markers, using the online database ‘HapMap’. We performed a frequency analysis of the mapped SNPs, followed by a linkage analysis using the HaploView software. Genotyping was performed using the High Resolution Melting technology. Results: The selected SNPs were in linkage disequilibrium. A significant difference between the three possible genotypes for rs3134105 was found for fT4/TSH ratio (P=0.03). Moreover, despite similar serum concentrations of fT3 and fT4 obtained by similar levothyroxine doses, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (P=0.04) as well as higher fT3/TSH (P=0.05) and fT4/TSH ratios (P=0.02). Conclusions: We demonstrated an association between TSH and discrete alleles of the TRHR gene identified by the markers SNPs rs3134105 and rs3110040 in totally thyroidectomized patients with diagnosis of thyroid cancer under subsuppressive LT4 therapy. The TRHR gene is a determinant of hypothalamo-pituitary sensitivity to levothyroxine in such patients.