A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine

Vijay Panicker, Christie Cluett, Beverley Shields, Anna Murray, Kirstie S. Parnell, John R B Perry, Michael N. Weedon, Andrew Singleton, Dena Hernandez, Jonathan Evans, Claire Durant, Luigi Ferrucci, David Melzer, Ponnusamy Saravanan, Theo J. Visser, Graziano Ceresini, Andrew T. Hattersley, Bijay Vaidya, Colin M. Dayan, Timothy M. Frayling

Research output: Contribution to journalArticle

Abstract

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 findingsweretakenforwardinto three additional studies in people not on T 4 (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/T 4 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 T3 vs. free T4 on a wide range of biological parameters.

Original languageEnglish (US)
Pages (from-to)3075-3081
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number8
DOIs
StatePublished - Aug 2008
Externally publishedYes

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Iodide Peroxidase
Triiodothyronine
Thyroxine
Genes
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
Thyroid Hormones
HapMap Project
Gene encoding
Alleles
Genome
Hormones
Serum

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. / Panicker, Vijay; Cluett, Christie; Shields, Beverley; Murray, Anna; Parnell, Kirstie S.; Perry, John R B; Weedon, Michael N.; Singleton, Andrew; Hernandez, Dena; Evans, Jonathan; Durant, Claire; Ferrucci, Luigi; Melzer, David; Saravanan, Ponnusamy; Visser, Theo J.; Ceresini, Graziano; Hattersley, Andrew T.; Vaidya, Bijay; Dayan, Colin M.; Frayling, Timothy M.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 8, 08.2008, p. 3075-3081.

Research output: Contribution to journalArticle

Panicker, V, Cluett, C, Shields, B, Murray, A, Parnell, KS, Perry, JRB, Weedon, MN, Singleton, A, Hernandez, D, Evans, J, Durant, C, Ferrucci, L, Melzer, D, Saravanan, P, Visser, TJ, Ceresini, G, Hattersley, AT, Vaidya, B, Dayan, CM & Frayling, TM 2008, 'A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine', Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 8, pp. 3075-3081. https://doi.org/10.1210/jc.2008-0397
Panicker, Vijay ; Cluett, Christie ; Shields, Beverley ; Murray, Anna ; Parnell, Kirstie S. ; Perry, John R B ; Weedon, Michael N. ; Singleton, Andrew ; Hernandez, Dena ; Evans, Jonathan ; Durant, Claire ; Ferrucci, Luigi ; Melzer, David ; Saravanan, Ponnusamy ; Visser, Theo J. ; Ceresini, Graziano ; Hattersley, Andrew T. ; Vaidya, Bijay ; Dayan, Colin M. ; Frayling, Timothy M. / A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 8. pp. 3075-3081.
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abstract = "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 findingsweretakenforwardinto three additional studies in people not on T 4 (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/T 4 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 T3 vs. free T4 on a wide range of biological parameters.",
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T1 - A common variation in deiodinase 1 gene DIO1 is associated with the relative levels of free thyroxine and triiodothyronine

AU - Panicker, Vijay

AU - Cluett, Christie

AU - Shields, Beverley

AU - Murray, Anna

AU - Parnell, Kirstie S.

AU - Perry, John R B

AU - Weedon, Michael N.

AU - Singleton, Andrew

AU - Hernandez, Dena

AU - Evans, Jonathan

AU - Durant, Claire

AU - Ferrucci, Luigi

AU - Melzer, David

AU - Saravanan, Ponnusamy

AU - Visser, Theo J.

AU - Ceresini, Graziano

AU - Hattersley, Andrew T.

AU - Vaidya, Bijay

AU - Dayan, Colin M.

AU - Frayling, Timothy M.

PY - 2008/8

Y1 - 2008/8

N2 - 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 findingsweretakenforwardinto three additional studies in people not on T 4 (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/T 4 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 T3 vs. free T4 on a wide range of biological parameters.

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