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Pathophysiological relevance of deiodinase polymorphism

Bianco, Antonio C.a; Kim, Brian S.b

Current Opinion in Endocrinology, Diabetes and Obesity: October 2018 - Volume 25 - Issue 5 - p 341–346
doi: 10.1097/MED.0000000000000428
THYROID: Edited by Lewis E. Braverman and Angela M. Leung

Purpose of review To assess new findings and clinical implications of deiodinase gene polymorphism. Deiodinases are enzymes that can activate or inactivate thyroid hormone molecules. Whereas the types 1 and 2 deiodinase (D1 and D2) activate thyroxine (T4) to 3,5,3′-triiodothyronine (T3) via deiodination of T4's outer ring, D1 and D3 inactivate both T4 and T3 and terminate thyroid hormone action via deiodination of T4's inner molecular ring. A number of polymorphisms have been identified in the three deiodinase genes; the most investigated and likely to have clinical relevance is the Thr92 substitution for Ala substitution in DIO2 (Thr92Ala-DIO2). There are a number of reports describing the association between the Thr92Ala-DIO2 polymorphism and clinical syndromes that include hypertension, type 2 diabetes, mental disorders, lung injury, bone turnover, and autoimmune thyroid disease; but these associations have not been reproduced in all population studies.

Recent findings A new report indicates that carriers of the Thr92Ala-DIO2 polymorphism exhibit lower D2 catalytic activity and localized/systemic hypothyroidism. This could explain why certain groups of levothyroxine-treated hypothyroid patients have improved quality of life when also treated with liothyronine (LT3). Furthermore, Ala92-D2 was abnormally found in the Golgi apparatus, what could constitute a disease mechanism independent of T3 signaling. Indeed, brain samples of Thr92Ala-DIO2 carriers exhibit gene profiles suggestive of brain degenerative disease. In addition, African American carriers of Thr92Ala-DIO2 exhibit an about 30% higher risk of developing Alzheimer's disease.

Summary The finding of deiodinase polymorphisms that can diminish thyroid hormone signaling and/or disrupt normal cellular function opens the door to customized treatment of hypothyroidism. Future studies should explore how the racial background modulates the clinical relevance of the Thr92Ala-DIO2 gene polymorphism.

aDivision of Endocrinology, University of Chicago

bDivision of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois, USA

Correspondence to Antonio C. Bianco, MD, PhD, Section of Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC1027, Room M267, Chicago, IL 60637, USA. Tel: +1 312 775 4493; E-mail:

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