A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine
Open accessAbstract
Introduction: Genetic factors influence circulating thyroid hormone levels, but the common gene variants involved have not been conclusively identified. The genes encoding the iodothyronine deiodinases are good candidates because they alter the balance of thyroid hormones. We aimed to thoroughly examine the role of common variation across the three deiodinase genes in relation to thyroid hormones. Methods: We used HapMap data to select single-nucleotide polymorphisms (SNPs) that captured a large proportion of the common genetic variation across the three deiodinase genes. We analyzed these initially in a cohort of 552 people on T4 replacement. Suggestive findings were taken forward into three additional studies in people not on T4 (total n = 2513) and metaanalyzed for confirmation. Results: A SNP in the DIO1 gene, rs2235544, was associated with the free T3 to free T4 ratio with genome-wide levels of significance (P = 3.6 × 10−13). The C-allele of this SNP was associated with increased deiodinase 1 (D1) function with resulting increase in free T3/T4 ratio and free T3 and decrease in free T4 and rT3. There was no effect on serum TSH levels. None of the SNPs in the genes coding for D2 or D3 had any influence on hormone levels. Conclusions: This study provides convincing evidence that common genetic variation in DIO1 alters deiodinase function, resulting in an alteration in the balance of circulating free T3 to free T4. This should prove a valuable tool to assess the relative effects of circulating free T3vs. free T4 on a wide range of biological parameters.
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The increase in fT3:fT4 ratio associated with this polymorphism is driven by decreased circulating fT4 and not an elevation in fT3 levels.
“the increase in fT3:fT4 ratio associated with this polymorphism is driven by the strong association with decreased circulating fT4 and not an elevation in fT3 levels; indeed, fT3 levels were not associated with the DIO1 polymorphism (64).”
From Liothyronine and Desiccated Thyroid Extract in the Treatment of Hypothyroidism (2020) · cites this paper as [64]
The Discussion (page unavailable) says the increased fT3/fT4 ratio is mainly driven by decreased fT4, supporting that part of the claim. But it also describes increased fT3 with the C allele, and the Results report an association between the polymorphism and fT3 in the WATTS cohort. The claim that fT3 levels were not associated is therefore not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPolymorphisms in DIO2 and DIO3 are not associated with serum TSH or thyroid hormone concentrations according to the most recent and largest studies.
“Polymorphisms in DIO2 and DIO3 are not associated with serum TSH or thyroid hormone concentrations according to the most recent and largest studies [54,55,57] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [57]
The C-allele of SNP rs2235544 in DIO1 is associated with increased D1 activity with resulting increase in serum free T3, decrease in serum free T4 and reverse T3 (rT3), and thereby in a decreased serum free T4 to free T3 concentration ratio.
“The C-allele of SNP rs2235544 in DIO1 is associated with increased D1 activity with resulting increase in serum free T3, decrease in serum free T4 and reverse T3 (rT3), and thereby in a decreased serum free T4 to free T3 concentration ratio.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [57]
This association is also observed in hypothyroid patients on L-T4 replacement.
“This is also observed in hypothyroid patients on L-T4 replacement ( table 5 ) [57] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [57]
In hypothyroid patients on L-T4 replacement, the DIO1 polymorphism rs2235544 is associated with the FT4/FT3 ratio (p for trend = 0.001).
“FT4/FT3 ratio | 5.79 | 5.44 | 5.22 | 0.001”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [57]
Variation in DIO1 is associated with the FT3:FT4 ratio but not TSH.
“Genetic association studies using variation in DIO1 which is associated with FT3:FT4 ratio but not TSH [111, 112] may also provide insights.”
From Age-related variation in thyroid function – a narrative review highlighting important implications for research and clinical practice (2023) · cites this paper as [111]
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“Genetic association studies using variation in DIO1 which is associated with FT3:FT4 ratio but not TSH [111, 112] may also provide insights.”
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- Authors
- Panicker, V., Cluett, C., Shields, B., Murray, A., Parnell, K. S., Perry, J. R. B., Weedon, M. N., Singleton, A., Hernandez, D., Evans, J., Durant, C., Ferrucci, L., Melzer, D., Saravanan, P., Visser, T. J., Ceresini, G., Hattersley, A. T., Vaidya, B., Dayan, C. M., & Frayling, T. M.
- Affiliations
- The University of Western Australia (AU)
- University of Exeter (GB)
- National Institutes of Health (US)
- University of Bristol (GB)
- Erasmus MC (NL)
- University of Parma (IT)
- Royal Devon and Exeter Hospital (GB)
- Corresponding author
- Dayan, Colin M.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2008-08-01
- Volume
- 93
- Issue
- 8
- Pages
- 3075-3081
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC2515080
- OpenAlex
- W2115160993
- Cited by
- 155
- References
- 29
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 13 · 2023: 11 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 6 · 2018: 2 · 2017: 12 · 2016: 8 · 2015: 7 · 2014: 9 · 2013: 5 · 2012: 12
- FWCI
- 7.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01 AG 24233-01, Z01AG000965, R01AG024233)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- DIO1, single nucleotide polymorphisms, free triiodothyronine, free thyroxine, reverse T3, genetic variation, thyroid-stimulating hormone
- MeSH terms
- Adult, Aged, Female, Humans, Iodide Peroxidase, Male, Middle Aged, Thyrotropin, Thyroxine, Triiodothyronine, Hormone Replacement Therapy, Polymorphism, Single Nucleotide
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