A meta-analysis of the associations between common variation in the PDE8B gene and thyroid hormone parameters, including assessment of longitudinal stability of associations over time and effect of thyroid hormone replacement
Open accessAbstract
Objective: Common variants in PDE8B are associated with TSH but apparently without any effect on thyroid hormone levels that is difficult to explain. Furthermore, the stability of the association has not been examined in longitudinal studies or in patients on levothyroxine (l-T 4). Design: Totally, four cohorts were used (n=2557): the Busselton Health Study (thyroid function measured on two occasions), DEPTH, EFSOCH (selective cohorts), and WATTS (individuals on l-T 4). Methods: Meta-analysis to clarify associations between the rs4704397 single nucleotide polymorphism in PDE8B on TSH, tri-iodothyronine (T 3), and T 4 levels. Results: Meta-analysis confirmed that genetic variation in PDE8B was associated with TSH (P=1.64×10−10 0.20 s.d./allele, 95% confidence interval (CI) 0.142, 0.267) and identified a possible new association with free T 4 (P=0.023, −0.07 s.d./allele, 95% CI −0.137, −0.01), no association was seen with free T 3 (P=0.218). The association between PDE8B and TSH was similar in 1981 (0.14 s.d./allele, 95% CI 0.04, 0.238) and 1994 (0.20 s.d./allele, 95% CI 0.102, 0.300) and even more consistent between PDE8B and free T 4 in 1981 (−0.068 s.d./allele, 95% CI −0.167, 0.031) and 1994 (−0.07 s.d./allele, 95% CI −0.170, 0.030). No associations were seen between PDE8B and thyroid hormone parameters in individuals on l-T 4. Conclusion: Common genetic variation in PDE8B is associated with reciprocal changes in TSH and free T 4 levels that are consistent over time and lost in individuals on l-T 4. These findings identify a possible genetic marker reflecting variation in thyroid hormone output that will be of value in epidemiological studies and provides additional evidence that PDE8B is involved in TSH signaling in the thyroid.
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The association between PDE8B and serum TSH is lost in subjects on thyroid hormone replacement.
“The association is lost in subjects on thyroid hormone replacement.”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [55]
Although thyroid hormone replacement may return an individual's serum TSH levels to within the reference range, this may be outside an individual's genetically determined set-point.
“This observation emphasizes that although thyroid hormone replacement may return an individual's serum TSH levels to within the reference range, this may be outside an individual's genetically determined set-point [55] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [55]
The findings on DIO1 polymorphisms have been replicated in two recent large studies (with p values below the threshold of 0.0033).
“The findings have been replicated in two recent large studies (with p values below the threshold of 0.0033) [54,55] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [55]
A recent meta-analysis confirmed that genetic variation in PDE8B is associated with serum TSH (+0.20 SD/allele), and identified a possible new association with free T4 (-0.07 SD/allele).
“A recent meta-analysis confirmed that genetic variation in PDE8B is associated with serum TSH (+0.20 SD/allele), and identified a possible new association with free T4 (-0.07 SD/allele) [55] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [55]
Polymorphisms 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 [55]
The Results section reports associations for PDE8B and DIO1, including no association between a DIO1 variant and TSH; it does not report findings for DIO2 or DIO3. Searches for DIO2, DIO3, and the claimed lack of association found no passage addressing either gene, so this copy cannot verify the claim. (LLM, conf=0.73)
Experimental — accuracy not yet measured
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 [112]
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- Authors
- Taylor, P. N., Panicker, V., Sayers, A., Shields, B., Iqbal, A., Bremner, A. P., Beilby, J. P., Leedman, P. J., Hattersley, A. T., Vaidya, B., Frayling, T., Evans, J., Tobias, J. H., Timpson, N. J., Walsh, J. P., & Dayan, C. M.
- Affiliations
- University of Bristol (GB)
- The University of Western Australia (AU)
- Southmead Hospital (GB)
- University of Exeter (GB)
- Pathwest Laboratory Medicine (AU)
- Royal Devon and Exeter Hospital (GB)
- Corresponding author
- Dayan, Colin M
- ORCID
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05
- Volume
- 164
- Issue
- 5
- Pages
- 773-780
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- PMC
- PMC3080745
- OpenAlex
- W2166634279
- Cited by
- 41
- References
- 26
- Citations by year
- 2026: 2 · 2025: 4 · 2023: 1 · 2022: 3 · 2021: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 6
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Research Exeter (University of Exeter) (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Figshare (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Explore Bristol Research (submittedVersion)
- Funders
- Medical Research Council (G0600705)
- 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
- PDE8B, thyroid-stimulating hormone, free thyroxine, triiodothyronine, thyroid hormone levels, single nucleotide polymorphisms, genetic association, levothyroxine, thyroid hormone replacement, Busselton Health Study, depth, Watt
- MeSH terms
- Adult, Aged, Female, Humans, Longitudinal Studies, Male, Middle Aged, Thyroid Hormones, Time Factors, Genetic Variation, 3',5'-Cyclic-AMP Phosphodiesterases, Cohort Studies, Hormone Replacement Therapy, Genetic Association Studies
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