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

Interesting to see another genetic basis for variation among us! (Must have missed it in 2014 as it is the sort of thing I would have posted then - had I seen it.)

These things always need a warning - even if these observations are absolutely rock solid, there could be any number of other variations which also impact on thyroid/TSH issues. As with the DIO2 gene, not having the genetic variant does not preclude an issue for other reasons!

Eur Thyroid J. 2014 Jun; 3(2): 101–108.

Published online 2014 Jun 7. doi: 10.1159/000358590

PMCID: PMC4109513

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

Giulia Brigante,a,c Giorgia Spaggiari,a,c Daniele Santi,a,c Katia Cioni,a,c Valentina Gnarini,a,c Chiara Diazzi,a,c Elisa Pignatti,a,b Livio Casarini,a,b Marco Marino,a,b Frank Tüttelmann,d Cesare Carani,a,c and Manuela Simonia,b,c,*



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.


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


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.


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).


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.

Key Words: TRHR, Hypothalamo-pituitary sensitivity, TSH suppression

The above is the abstract taken from the full paper which is freely available here:

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Having a clean up of unanswered posts. :)



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