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Novel insights into thyroid hormones from the study of common genetic variation

Abstract

Effects of thyroid hormones in individual tissues are determined by many factors beyond their serum levels, including local deiodination and expression and activity of thyroid hormone transporters. These effects are difficult to examine by traditional techniques, but a novel approach that exploits the existence of common genetic variants has yielded new and surprising insights. Convincing evidence indicates a role of type 1 iodothyronine deiodinase (D1) in determining the serum T4:T3 ratio and a role of phosphodiesterase 8B in determining TSH levels. In addition, studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence Intelligence quotient alterations associated with iodine deficiency. Preliminary evidence suggests associations between TSH-receptor variants and fasting glucose level, D1 variants and insulin-like growth factor I production, and D2 variants and hypertension, psychological well-being and response to T3 or T4 treatment. Intriguingly, most of these associations are independent of serum thyroid hormone levels, which highlights the importance of local regulation of thyroid hormones in tissues. Future research might reveal novel roles for thyroid hormones in obesity, cardiovascular disease, osteoporosis and depression and could have implications for interpretation of thyroid function tests and individualization of thyroid hormone replacement therapy.

Key Points

  • Various processes influence the action of thyroid hormones in different tissues, such as local deiodination and transport of thyroid hormones across cell membranes, independently of serum thyroid hormone levels

  • Studies of commonly inherited variations have shown that the genes encoding type 1 iodothyronine deiodinase and phosphodiesterase 8B are important determinants of baseline serum thyroid hormone and TSH levels

  • Polymorphisms that affect the thyroid hormone pathway influence osteoarthritis and a highly suggestive association has been reported between these polymorphisms and the neurodevelopmental response to iodine deficiency

  • Polymorphisms might influence fasting glucose level, insulin-like growth factor I level, hypertension, psychological well-being and response to replacement therapy; many of these effects are independent of serum T3/T4 levels

  • Studies of common genetic variation in large, diverse cohorts are likely to provide important novel insights into the role of thyroid hormones in health and disease

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Figure 1: The thyroid hormone pathway.

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Acknowledgements

The authors are grateful for very helpful discussions with the following people: J Evans, G Lewis, A Hattersley and T Frayling from the Peninsula Medical School, Exeter, UK; P Saravanan at the University of Warwick, UK; R Greenwood at United Healthcare Bristol, UK; O Bjerkeset, T Bjoro and B Asvold, HUNT research center, Norway; and T Visser and his research team at Erasmus University Medical Centre, The Netherlands. V Panicker is supported by an A & A Saw Medical Research Fellowship through the Faculty of Medicine, Dentistry and Health Sciences at the University of Western Australia.

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Correspondence to Colin M. Dayan.

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Dayan, C., Panicker, V. Novel insights into thyroid hormones from the study of common genetic variation. Nat Rev Endocrinol 5, 211–218 (2009). https://doi.org/10.1038/nrendo.2009.19

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