A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels
Open accessAbstract
Objective: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45–65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT 4) levels. Design and methods: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT 4 levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. Results: For TSH, eight PDE8B polymorphisms (P=4×10−17) remained significant in the meta-analysis. For FT 4, two DIO1(P=8×10−12) and one FOXE1(P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1(P=0.0028) and three THRB(P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT 4, but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively). Conclusions: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B,THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT 4 levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT 4 levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.
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A large number of SNPs in other genes involved in thyroid hormone pathways (including sulfatases and thyroid hormone transporters) have been investigated, but none was associated with serum TSH or free T4.
“A large number of SNPs in other genes involved in thyroid hormone pathways (including sulfatases and thyroid hormone transporters) have been investigated, but none was associated with serum TSH or free T4 [54] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [54]
The Results passage in our copy reports that 1,512 polymorphisms across 68 thyroid hormone pathway genes were investigated. It reports significant associations for PDE8B, DIO1 and FOXE1, and a suggestive FT4 association for the transporter gene SLC16A10 that did not meet the corrected significance threshold. Thus, the blanket statement that none was associated is too strong; the available passage also does not identify sulfatases among the genes tested. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA meta-analysis of 1,512 studied polymorphisms in 68 thyroid hormone pathway genes in four populations showed a significant association of 30 SNPs in 10 genes with TSH; only 8 SNPs in PDE8B remained significant with p values below the threshold of 0.0022.
“A meta-analysis of 1,512 studied polymorphisms in 68 thyroid hormone pathway genes in four populations showed a significant association of 30 SNPs in 10 genes with TSH; only 8 SNPs in PDE8B remained significant with p values below the threshold of 0.0022 [54] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [54]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThe 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 [54]
Subsequent studies also reported the association between PDE8B and higher serum TSH, but not between PDE8B and serum free T4 which would have expected to be lower.
“Subsequent studies also reported the association between PDE8B and higher serum TSH, but not between PDE8B and serum free T4 which would have expected to be lower [53,54] .”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [54]
The indexed copy returned only a bibliographic abstract (no section or page), ending mid-sentence, rather than a full-text passage. Searches for PDE8B’s association with TSH and its lack of association with FT4 found no Results or Discussion passage in our copy that could verify the claim. (LLM, conf=0.76)
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 [54]
The available passages have no section or page labels and do not report results for DIO2 or DIO3. Searches for both genes and for their association with TSH and FT4 returned no gene-specific findings; the listed significant associations alone cannot establish that DIO2 and DIO3 were not associated. (LLM, conf=0.72)
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References 41 · Cited by 68
- Authors
- Medici, M., van der Deure, W. M., Verbiest, M., Vermeulen, S. H., Hansen, P. S., Kiemeney, L. A., Hermus, A. R. M. M., Breteler, M. M., Hofman, A., Hegedüs, L., Kyvik, K. O., Heijer, M. D., Uitterlinden, A. G., Visser, T. J., & Peeters, R. P.
- Affiliations
- Erasmus MC (NL)
- ORCID
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-05
- Volume
- 164
- Issue
- 5
- Pages
- 781-788
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2115317383
- Cited by
- 68
- References
- 41
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 1 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 12
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- 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
- serum TSH, free thyroxine, genetic polymorphism, PDE8B, DIO1, FOXE1, thyroid hormone receptor beta, genetic association
- MeSH terms
- Adult, Aged, Female, Humans, Male, Middle Aged, Population Surveillance, Prospective Studies, Thyroid Hormones, Thyroxine, Genetic Variation, Cohort Studies, Signal Transduction, Forkhead Transcription Factors, Genetic Association Studies
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