No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

Wouters, Hanneke J.C.M.; van Loon, Hannah C.M.; van der Klauw, Melanie M.; Elderson, Martin F.; Slagter, Sandra N.; Kobold, Anneke Muller; Kema, Ido P.; Links, Thera P.; van Vliet-Ostaptchouk, Jana V.; Wolffenbuttel, Bruce H.R.

doi:10.1089/thy.2016.0199

Cited by 97Thyroid Disorders and TreatmentsGenetic Associations and EpidemiologyThyroid Cancer Diagnosis and Treatment

No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

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Wouters, Hanneke J.C.M., van Loon, Hannah C.M., van der Klauw, Melanie M., Elderson, Martin F., Slagter, Sandra N., Kobold, Anneke Muller, Kema, Ido P., Links, Thera P. +2 more·2017·Thyroid®

DOI 10.1089/thy.2016.0199

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Abstract

Introduction: The presence of the Thr92Ala polymorphism of deiodinase-2 (D2) has been thought to have several effects. It may influence its enzymatic function, is associated with increased expression of genes involved in oxidative stress in brain tissue, and may predict favorable response to combination levothyroxine (LT4) plus triiodothyronine (T3) therapy. It was hypothesized that homozygous carriers of the D2-92Ala allele have different thyroid hormone parameters, and reduced health-related quality of life (HRQoL) and cognitive functioning. Methods: In 12,625 participants from the LifeLines cohort study with genome-wide genetic data available, the effects of the Thr92Ala polymorphism (rs225014) were evaluated in the general population and in 364 people treated with thyroid hormone replacement therapy, the latter mainly because of primary hypothyroidism. In addition to evaluating anthropometric data, medication use, and existence of metabolic syndrome, HRQoL was assessed with the RAND 36-Item Health Survey, and the Ruff Figural Fluency Test was used as a sensitive test for executive functioning. Data on thyrotropin, free thyroxine (fT4), and free T3 (fT3) levels were available in a subset of 4479 participants. Results: The mean age (±standard deviation) was 53 ± 12 years and the body mass index was 27.0 ± 4.5 kg/m 2 in the LT4 users compared with 48 ± 11 years and 26.2 ± 4.1 kg/m 2 in participants from the general population. The Ala/Ala genotype of the D2-Thr92Ala polymorphism was present in 11.3% of LT4 users and in 10.7% of the general population. In total, 3742/4479 subjects with thyroid hormone data available had normal TSH (0.4–4.0 mIU/L), and 88% of LT4 users were females. LT4 users had higher fT4, lower fT3, and a lower fT3/fT4 ratio, and female patients had lower scores on the HRQoL domains of physical functioning, vitality, mental health, social functioning, bodily pain, and general health compared with those not using LT4 ( p < 0.005). Executive functioning scores, as part of cognitive functioning, were comparable between female LT4 users and the general population. In both groups, the D2-Thr92Ala polymorphism was not associated with differences in TSH, fT4, fT3, the fT3/fT4 ratio, presence of metabolic syndrome or other comorbidities, use of medication, HRQoL, and cognitive functioning. Conclusion: The Thr92Ala polymorphism of D2 was not associated with thyroid parameters, HRQoL, and cognitive functioning in the general population and in participants on thyroid hormone replacement therapy.

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The DIO2 Thr92Ala polymorphism has no effects on differences in thyroid hormone parameters, health-related QoL, and cognitive functioning.
“The Ala/Ala genotype of the DIO2 Thr92Ala polymorphism is present in 11% of both LT4 users and the general population, although without effects on differences in thyroid hormone parameters, health-related QoL, and cognitive functioning [78].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [78]
The Ala/Ala genotype of the DIO2 Thr92Ala polymorphism is present in 11% of both LT4 users and the general population.
“The Ala/Ala genotype of the DIO2 Thr92Ala polymorphism is present in 11% of both LT4 users and the general population, although without effects on differences in thyroid hormone parameters, health-related QoL, and cognitive functioning [78].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [78]
A subsequent study failed to replicate our findings but was potentially underpowered-had fewer subjects on LT4 (n = 364).
“A subsequent study failed to replicate our findings but was potentially underpowered—had fewer subjects on LT4 (n = 364) (43).”
From Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design (2023) · cites this paper as [43]
Th92Ala-DIO2 genotype had no impact on response to LT4 monotherapy in terms of health-related QoL or cognitive function or in the general population.
“did not find any impact of Th92Ala-DIO2 genotype on the response to LT4 monotherapy in terms of health-related QoL or cognitive function or an effect in the general population [25].”
From Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document (2021) · cites this paper as [25]
The absence of an association between DIO2 genotype and thyroid hormone level was confirmed in many other studies.
“Indeed, the absence of an association between the genotype and thyroid hormone level was confirmed in many other studies [ 93 , 97 – 99 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [99]

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Relationship Between Body Composition and Quality of Life in Young Patients With Differentiated Thyroid Carcinoma After Thyroidectomy
Schock, C. T. F., Antunes‐Correa, L. M., Juliani, F. L., Souza, M. A. D. S., Carvalheira, J. B. C., Bahamondes, L., & Zantut‐Wittmann, D. E. (2026) · International Journal of Endocrinology · doi:10.1155/ije/9268141
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No effect of Thr92Ala DIO2 polymorphisms on thyroid parameters, health-related quality of life, and cognitive functioning
Wolffenbuttel, B. H. R., van, L. H. C. M., Elderson, M. F., van Vliet‐Ostaptchouk, J. V., Wouters, H. J. C. M., Kobold, A. C. M., Links, T. P., Slagter, S. N., & van, D. K. M. (2015) · Endocrine Abstracts · doi:10.1530/endoabs.37.gp.26.09
Self-citation
Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis
Heemstra, K. A., Hoftijzer, H. C., Van Der Deure, W. M., Peeters, R. P., Fliers, E., Appelhof, B. C., Wiersinga, W. M., Corssmit, E. P. M., Visser, T. J., & Smit, J. W. A. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2008.03474.x · Cited by 51 · see citing works
Type 2 Deiodinase A/G (Thr92Ala) Polymorphism and Circulating Thyroid Hormone Level of Childbearing Age Women in Area Replete with Iodine Deficiency Disorders
Wibowo, A., Hidayat, T., & Wahyuningrum, S. S. (2022) · Open Access Macedonian Journal of Medical Sciences · doi:10.3889/oamjms.2022.11017
Pathophysiological relevance of deiodinase polymorphism
Bianco, A. C., & Kim, B. S. (2018) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000428 · Cited by 59 · see citing works
Type 2 deiodinase Thr92Ala polymorphism and aging are associated with a decreased pituitary sensitivity to thyroid hormone
Luongo, C., De Stefano, M. A., Ambrosio, R., Volpe, F., Porcelli, T., Golia, V., Bellevicine, C., Troncone, G., Masone, S., Damiano, V., et al. (2023) · Thyroid · doi:10.1089/thy.2022.0472 · Cited by 11 · see citing works

Authors: Wouters, H. J. C. M., van Loon, H. C. M., van der Klauw, M. M., Elderson, M. F., Slagter, S. N., Kobold, A. M., Kema, I. P., Links, T. P., van Vliet-Ostaptchouk, J. V., & Wolffenbuttel, B. H. R.
Affiliations: University Medical Center Groningen (NL)
University Medical Center Groningen
Corresponding author: Wolffenbuttel, Bruce H.R.
ORCID: Wouters, Hanneke J.C.M.
Kema, Ido P.
Links, Thera P.
Wolffenbuttel, Bruce H.R.
Venue: Thyroid®
Publisher: SAGE Publications
Published: 2017-02
Volume: 27
Issue: 2
Pages: 147-155
ISSN: 1050-7256 (ISSN-L)
1557-9077
DOI: 10.1089/thy.2016.0199
OpenAlex: W2542430691
Cited by: 97
References: 46
Citations by year: 2026: 5 · 2025: 5 · 2024: 4 · 2023: 13 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 10 · 2018: 13 · 2017: 8
FWCI: 10.36
Type: journal article
Language: en
Open access: green
research.rug.nl
Licence: other-oa
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Thyroid (publishedVersion)
PubMed (publishedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords: deiodinase 2, health-related quality of life, cognitive function, executive function, levothyroxine, triiodothyronine, free thyroxine, primary hypothyroidism, thyroid hormone replacement, Lifelines cohort, genetic association
MeSH terms: Iodothyronine Deiodinase Type II, Adult, Aged, Cognition, Female, Health Status, Humans, Hypothyroidism, Iodide Peroxidase, Male, Middle Aged, Quality of Life, Thyrotropin, Thyroxine, Triiodothyronine, Cohort Studies, Case-Control Studies, Polymorphism, Single Nucleotide

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No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study

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