Gene polymorphisms and thyroid hormone signaling: implication for the treatment of hypothyroidism

• Published in: Endocrine Vol. 84; no. 2; pp. 309 - 319
• Main Authors: Penna, Gustavo C., Salas-Lucia, Federico, Ribeiro, Miriam O., Bianco, Antonio C.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2024; Springer Nature B.V
• Subjects: Diabetes; Endocrinology; Gene polymorphism; Humanities and Social Sciences; Hypothyroidism; Internal Medicine; Medicine; Medicine & Public Health; multidisciplinary; Mutation; Patients; Review; Science; Single-nucleotide polymorphism; Thyroid gland; Thyroxine; Triiodothyronine; T3-signaling; thyroxine; polymorphism; thyroid; triiodothyronine; deiodinase
• ISSN: 1559-0100; 1355-008X; 1559-0100
• DOI: 10.1007/s12020-023-03528-y

Introduction Mutations and single nucleotide polymorphisms (SNPs) in the genes encoding the network of proteins involved in thyroid hormone signaling (TH) may have implications for the effectiveness of the treatment of hypothyroidism with LT4. It is conceivable that loss-of-function mutations or SNPs impair the ability of LT4 to be activated to T3, reach its targets, and ultimately resolve symptoms of hypothyroidism. Some of these patients do benefit from therapy containing LT4 and LT3. Methods Here, we reviewed the PubMed and examined gene mutations and SNPs in the TH cellular transporters, deiodinases, and TH receptors, along with their impact on TH signaling, and potential clinical implications. Results In some mechanisms, such as the Thr92Ala-DIO2 SNP, there is a compelling rationale for reduced T4 to T3 activation that limits the effectiveness of LT4 to restore euthyroidism. In other mechanisms, a potential case can be made but more studies with a larger number of individuals are needed. Discussion/Conclusion Understanding the clinical impact of the genetic makeup of LT4-treated patients may help in the preemptive identification of those individuals that would benefit from therapy containing LT3.