Pathophysiological relevance of deiodinase polymorphism
Open accessAbstract
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.
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The proposed role played by the Thr92Ala DIO2 polymorphism was not reproduced in all populations.
“The proposed role played by the Thr92Ala DIO2 polymorphism was not reproduced in all populations (30).”
From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [30]
A SNP in the type 2 deiodinase gene (p.Thr92Ala) is associated with hypertension, T2DM, insulin resistance, and BMI.
“For instance, a single-nucleotide polymorphism in the type 2 deiodinase gene (p.Thr92Ala) has been found to be associated with hypertension, type 2 diabetes mellitus (T2DM), insulin resistance, and body mass index (BMI) [68].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [68]
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“Further research will be needed to confirm whether genetic variations in deiodinases, and indeed in other sites of cellular access or action of thyroid hormones (such as membrane transporters, nuclear receptors and other sites) may facilitate individualised treatment of hypothyroid patients in the future [44,50-52].”
BackgroundResult
- Authors
- Bianco, A. C., & Kim, B. S.
- Affiliations
- University of Chicago (US)
- Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois, USA
- Corresponding author
- Bianco, Antonio C.
- ORCID
- Bianco, Antonio C.
- Venue
- Current Opinion in Endocrinology, Diabetes & Obesity
- Published
- 2018-10
- Volume
- 25
- Issue
- 5
- Pages
- 341-346
- ISSN
- 1752-296X (ISSN-L)
- 1752-2978
- PMC
- PMC6571023
- OpenAlex
- W2887168676
- Cited by
- 59
- References
- 52
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 4 · 2023: 8 · 2022: 11 · 2021: 12 · 2020: 3 · 2019: 8
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Endocrinology Diabetes and Obesity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058538, R56DK058538, R01DK065055)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- DIO2, type 2 deiodinase, type 3 deiodinase, thyroid hormone metabolism, hypothyroidism, liothyronine, levothyroxine, Alzheimer's disease, Golgi apparatus, neurodegenerative diseases, hypertension, type 2 diabetes, autoimmune thyroid disease
- MeSH terms
- Iodothyronine Deiodinase Type II, Brain Diseases, Metabolic, Endocrine System Diseases, Humans, Hypothyroidism, Iodide Peroxidase, Nerve Degeneration, Polymorphism, Genetic, Quality of Life, Syndrome, Thyroxine, Triiodothyronine
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