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Phosphodiesterase 8B Gene Variants Are Associated with Serum TSH Levels and Thyroid Function
Open accessAbstract
Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a prim…
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“Phosphodiesterase 8B gene (PDE8B) variants are associated with serum TSH (e.g. each additional copy of the minor allele of rs4704397 is associated with an increase of 0.13 mU/l in serum TSH [52] ).”
From 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism (2012) · cites this paper as [52]
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Metadata
- Authors
- Arnaud-Lopez, L., Usala, G., Ceresini, G., Mitchell, B. D., Pilia, M. G., Piras, M. G., Sestu, N., Maschio, A., Busonero, F., Albai, G., Dei, M., Lai, S., Mulas, A., Crisponi, L., Tanaka, T., Bandinelli, S., Guralnik, J. M., Loi, A., Balaci, L., Sole, G., Prinzis, A., Mariotti, S., Shuldiner, A. R., Cao, A., Schlessinger, D., Uda, M., Abecasis, G. R., Nagaraja, R., Sanna, S., & Naitza, S.
- Affiliations
- National Institute on Aging (US)
- National Research Council (IT)
- University of Parma (IT)
- University of Maryland, Baltimore (US)
- Azienda Sanitaria di Firenze (IT)
- National Institutes of Health (US)
- University of Cagliari (IT)
- University of Michigan (US)
- Corresponding author
- Naitza, Silvia
- ORCID
- Ceresini, Graziano
- Mitchell, Braxton D.
- Piras, Maria Grazia
- Maschio, Andrea
- Busonero, Fabio
- Dei, Mariano
- Lai, Sandra
- Mulas, Antonella
- Crisponi, Laura
- Bandinelli, Stefania
- Guralnik, Jack M.
- Sole, Gabriella
- Mariotti, Stefano
- Shuldiner, Alan R.
- Schlessinger, David
- Uda, Manuela
- Abecasis, Gonçalo R.
- Nagaraja, Ramaiah
- Sanna, Serena
- Naitza, Silvia
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 82
- Issue
- 6
- Pages
- 1270-1280
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2427267
- OpenAlex
- W2170941644
- Cited by
- 139
- References
- 53
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 8 · 2016: 3 · 2015: 11 · 2014: 9 · 2013: 14 · 2012: 21
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Funders
- National Institutes of Health (263-MA-410953, NO1-AG-1–2109)
- National Institute on Aging
- National Center for Research Resources
- Johns Hopkins University (M01 RR 000052)
- Geriatric Research Education and Clinical Center
- Ministero della Salute (ICS 110.1/RS97.71)
- University of Michigan (HG002651, HL084729)
- Fondazione Banco di Sardegna
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- PDE8B, thyroid-stimulating hormone, serum TSH levels, thyroid function, single nucleotide polymorphisms, intron 1, cyclic AMP, PDE10A, TSH receptor, thyroid hormone receptor beta, GNAQ, TG, Pit-1, PDE4D, thyroid dysfunction
- MeSH terms
- Cyclic AMP, Adolescent, Adult, Aged, Aged, 80 and over, Chromosome Mapping, Feedback, Female, Humans, Male, Middle Aged, Pituitary Gland, Thyroid Diseases, Thyroid Gland, Thyrotropin, Thyroxine, Triiodothyronine, Genetic Variation, 3',5'-Cyclic-AMP Phosphodiesterases, Linkage Disequilibrium, Polymorphism, Single Nucleotide
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