Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

in European Journal of Endocrinology

Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.

Abstract

Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.

Introduction

Thyroid hormone is essential for growth and differentiation, for the regulation of energy metabolism, and for the physiological function of virtually all human tissues. The production of thyroid hormone is regulated by the classic hypothalamus–pituitary–thyroid axis, whereas the biological activity of thyroid hormone (i.e. the availability of the active hormone triiodothyronine (T3) for the nuclear thyroid hormone receptors) is mainly regulated at the tissue level by the iodothyronine deiodinases and thyroid hormone transporters.

In healthy subjects, serum thyroid parameters show substantial inter-individual variability, whereas the intra-individual variability is within a narrow range (1). This suggests an important influence of genetic variation, in addition to environmental factors such as food or iodine intake, on the regulation of thyroid hormone bioactivity, resulting in a thyroid function set-point that is different for each individual. This notion is supported by a classical twin study that was recently published (2). In this study, heritabilityaccounted for ~65% of the variation in serum thyroid stimulating hormone (TSH), free thyroxine (FT4), and free T3 (FT3) levels. In a Mexican–American population, total heritability in serum thyroid parameters ranged from 26 to 64% of the total inter-individual variation observed (3).

Findings in patients with subclinical hyper- and hypothyroidism illustrate that even minor alterations in thyroid hormone levels (and in thyroid hormone bioactivity) can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate (46). In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that result in an altered thyroid hormone bioactivity. Some of these polymorphisms are associated with serum TSH and/or thyroid hormone levels in healthy subjects, and/or with thyroid hormone-related clinical endpoints. As DNA variations are stable throughout life, such genetic effects are likely to have an influence during the lifetime of subjects.

In this review, we discuss the genetic variation in thyroid hormone pathway genes, focusing on the polymorphism studies that have emerged in the last few years. For the sake of brevity, we have focused on single nucleotide polymorphisms (SNPs) in the TSH receptor and iodothyonine deiodinases, since only these genes are presently analyzed for possible associations with serum thyroid hormone levels. Besides their relation with serum thyroid hormone levels, we discuss the effects of these polymorphisms on clinical endpoints such as Graves’ disease and insulin resistance. Furthermore, we discuss the possible consequences of these studies for the individual patient, and also the new insights in thyroid hormone action that can be obtained from these data.

Polymorphisms in the TSH receptor

Many somatic gain-of-function mutations in the TSH receptor (TSHR) have been described, which result in a phenotype of toxic adenoma or toxic multinodular goiter (7). Germline gain-of-function TSHR mutations that result in congenital hyperthyroidism have also been described. Conversely, germline loss-of-function TSHR mutations are associated with TSH resistance and congenital hypothyroidism (see reference (8) for an illustrative example). However, only three germline TSHR polymorphisms, resulting in amino acid substitutions, have been identified (911). Two of these are located in the extracellular domain of the receptor (Asp36His and Pro52Thr) (9, 10), and one is located in the intracellular domain (Asp727Glu) (11) (Fig. 1). In addition, several intronic microsatellite markers and intronic SNPs have been described in TSHR (1216).

The TSHR-Glu727 allele was associated with lower levels of plasma TSH in a population of healthy blood donors, but had no effect on FT4 (17). Recently, we have confirmed this observation in unrelated study populations (18, 19). This could point toward a higher sensitivity of the variant versus the wild-type TSHR, since less TSH is needed to produce normal FT4 levels. Although there is one in vitro study showing that the TSHR-Glu727 variant results in an increased cAMP response of the receptor to TSH (11), others have not been able to replicate this (20, 21). A different explanation would be that the Asp727Glu polymorphism is linked to another polymorphism elsewhere in the gene. The TSHR-Asp727Glu polymorphism is found to be within a linkage disequilibrium block starting at intron 8 and extending about 10 kb beyond the 3′UTR of the TSHR gene (22).

Conflicting data are also available regarding the response of the TSHR-Pro52Thr variant to TSH stimulation (2325). This might reflect the subtle effects of these polymorphisms. The TSHR-Pro52Thr and -Asp36His polymorphisms were not associated with changes in serum TSH or iodothyronine levels in healthy blood donors. However, this could be attributable to the low allele frequency of these SNPs (6 and 0.6% respectively) resulting in a lack of power.

No data on polymorphisms resulting in a relative loss of function of the TSHR are yet available. Subjects with a heterozygous loss of function mutation appear to have a dominant transmission of partial TSH resistance, which is due to intracellular entrapment and reduced maturation of the wild-type TSHR by the inactive mutants (26). Similarly, polymorphisms resulting in a relative loss of function could have an impact via this mechanism, and possibly account for some of the so-called ‘euthyroid outliers’ with elevated TSH determinations.

Besides effects on serum thyroid hormone levels, polymorphisms in the TSHR may also have effects on the development of autoimmune thyroid disease. The TSHR gene is located on chromosome 14q31, an area in which a Graves’ disease susceptibility locus (GD-1) has been mapped (27). The GD-1 locus is specifically linked to Graves’ disease, but not Hashimoto’s thyroiditis or autoimmune thyroid disease in general. Several case-control studies have been carried out analyzing the possible association between one or more of the previously mentioned TSHR polymorphisms and autoimmune thyroid disease. An overview of the 14 studies up to 2002 that analyzed the possible association of TSHR polymorphisms with Graves’ disease has been presented by Ban et al. (28).

All studies analyzing the TSHR-Pro52Thr or Asp36His variant showed no association, apart from one in which an association of the TSHR-Pro52Thr variant with Graves’ disease was described in US Caucasian females (n = 100 females with autoimmune thyroid disease versus 69 controls) (29). These same authors later described two subjects who were homozygous for the Thr52 allele and had normal thyroid function tests, on the basis of which they suggested that the variant receptor is able to respond normally to TSH (23). Obviously, more subtle effects of this polymorphism cannot be excluded by the last study. In a multiethnic (Chinese, Malays, and Indians) cohort of patients with Graves’ disease, TSHR-Asp36His was absent, and TSHR-Pro52Thr and -Asp727Glu were not associated with Graves’ disease (30). Unfortunately, no data are presently available if the two variants in the extracellular domain of the receptor show altered binding of thyroid-stimulating antibodies. Nor are any data available regarding altered binding or altered cAMP response of the variant TSH receptor to a different TSHR ligand termed thyrostimulin that has recently been identified (31).

Three case-control studies in Caucasians showed no association between the TSHR-Asp727Glu polymorphism and Graves’ disease (11, 28, 32). However, meta-analysis of these three studies (28), as well as a study in Russian patients (n = 78 vs 93 controls), showed a weak association of the variant receptor with Graves’ disease (33, 34). These Graves’ patients showed a significantly higher frequency of the TSHR-Glu727 allele than did healthy subjects (33, 34). A recent transmission disequilibrium test (TDT) study in Russian families showed that the D2-Thr92Ala (see below) and TSHR-Asp727Glu polymorphisms are in weak linkage disequilibrium (35), and that the D2-Ala92/TSHR-Glu727 haplotype allele was preferentially transmitted from parents to affected siblings with Graves’ disease (35). However, TDT is not the best design to analyze linkage disequilibrium.

A recent study in Japanese patients with autoimmune thyroid disease showed that several SNPs in intron 7 of the TSHR gene are significantly associated with Graves’ disease (14). Another polymorphism in intron 4 of TSHR was associated with Graves’ disease in a multiethnic population of patients from Singapore (30). Recently, a study in which common haplotype tagging SNPs in TSHR were analyzed showed a significant association of intronic SNPs in one linkage disequilibrium block with Graves’ disease (22).

These data together suggest that genetic variation in TSHR is, albeit weakly, associated with the development of Graves’ disease, but it is yet unclear whether the associated polymorphisms are functional or whether they are linked to functional variants elsewhere in the gene or in the nearby genome that are still to be discovered. Meta-analysis, detailed linkage disequilibrium analysis, and haplotype tagging approaches (as well as the HapMap project, www.hapmap.org) should be able to resolve this issue (36).

TSHR is not only expressed in the thyroid, but also in adipose tissue (37), brain (38), orbital tissue (37, 39), lymphocytes (40), and bone (41). Evidence is accumulating for direct effects of TSH via the TSHR on these tissues. TSH is able to induce proliferation and inhibit differentiation in cultured rat pre-adipocytes (42), and TSHR knockout mice have a severe phenotype of osteoporosis, independent of their thyroid hormone levels (41). Genetic variation in TSHR may thus not only be important for the development of autoimmune thyroid disease (more specifically Graves’ disease), but may also be associated with more common clinical endpoints such as osteoporosis (19), either via its influence on thyroid hormone levels, or via direct effects of TSH on bone.

Polymorphisms in the iodothyronine deiodinases

No patients with inactivating mutations in any of the iodothyronine deiodinases have yet been described. Whether this means that these mutations are not compatible with life, that they have little or no consequences, or that they result in unexpected phenotypes is unclear. Based on the phenotypes of mice with targeted deletions of D1, D2, or D3, the most severe effects would be expected of mutations in D3 (4345). In the last few years, several polymorphisms in deiodinases have been described (17, 46, 47) (Fig. 1). Based on the physiological role of the three different deiodinases (48) (Table 1), one can speculate about the possible consequences of polymorphisms in these enzymes. D1 is present in liver, kidney, and thyroid, and plays a key role in the production of the active hormone T3 from T4 and in the clearance of the metabolite reverse T3 (rT3) (48, 49). D2 is present in brain, pituitary, brown adipose tissue, thyroid, skeletal muscle, aortic smooth muscle cells, and osteoblasts; D2 mRNA has also been detected in the human heart (48). In tissues such as the brain, D2 is important for local production of T3, whereas D2 in skeletal muscle may also contribute to plasma T3 production. D3 is present in brain, skin, placenta, pregnant uterus, and various fetal tissues, and is induced in critical illness (48, 50). D3 is the major T3 and T4 inactivating enzyme and contributes to thyroid hormone homeostasis by protecting tissues from excess thyroid hormone. The T3/rT3 ratio is considered to be a sensitive indicator of the peripheral metabolism of thyroid hormone, being positively influenced by D1 and D2 and negatively by D3. This ratio is also relatively independent of thyroidal T4 production and of variations in serum binding proteins. In addition to genetic variation, the peripheral metabolism of thyroid hormone can be influenced by factors such as iodine deficiency, nutritional status, and disease.

D1

Recently, two polymorphisms in D1 (D1-C785T and D1-A1814G) that affect the serum T3/rT3 ratio in healthy subjects have been identified (17) (Fig. 1). The D1-785T allele is associated with higher levels of rT3 and with a lower T3/rT3 ratio. Based on the function of D1 (Table 1), it was speculated that the D1-785T variant results in a decreased activity of D1. The D1-1814G allele was associated with a higher T3/rT3 ratio, suggesting that the D1-1814G variant may result in increased activity (17). Since both polymorphisms are located in the 3′-UTR of the mRNA, a change in the stability of the mRNA is an attractive explanation for their effect. Alternative explanations include an altered folding of the mRNA, in particular of the selenocysteine insertion sequence (SECIS), which is necessary for the incorporation of a selenocysteine residue in the catalytic center of the protein (48), or linkage with other polymorphisms in the coding sequence or in regulatory regions of the gene. Functional testing and haplotype analysis will be necessary to resolve this issue. Although the D1-785T variant is not associated with serum rT3 levels in a population of 350 elderly men (age > 70 years), its association with lower levels of T3 in this elderly population supports the hypothesis of a lower activity of D1 in carriers of this polymorphism (51). The difference in associations found in the healthy blood donors and the elderly men might be explained by the difference in age, with means of 46 vs 77 years respectively. In young subjects, a decreased T3 production by D1 may be masked by the production of serum T3 by skeletal muscle D2. Throughout adult life, skeletal muscle size and strength gradually decline, resulting in a decrease in D2-expressing skeletal muscle. Furthermore, rT3 levels increase with age, and degradation of the D2 protein is accelerated when it is exposed to its own substrates T4 and rT3 (52). Although it has been shown that D1 activity also decreases during aging (53), the relative contribution of D2 to serum T3 production may be less important in the elderly than in young subjects. This would mean that D1 has a relatively greater contribution to serum T3 production at advanced ages (51) (Fig. 2). In line with this hypothesis is the recent publication of a polymorphism in a short open reading frame (ORFa) in the 5′-UTR of D2, which has been shown to be an important regulatory element (47, 54) (Fig. 2). This polymorphism (D2-ORFa-Gly3Asp) is associated with the serum T3/T4 ratio in young, but not elderly, subjects (47). Also supporting this hypothesis is the association of the D1-C785T polymorphism with both serum T3 and rT3 levels in an unrelated third population, with an average age of 69 years (RP Peeters, WM van der Deure, TJ Visser, unpublished observations).

Haplotype analysis showed that the D1-C785T and D1-A1814G polymorphisms appear on different haplotype alleles (17, 51). The haplotype allele containing D1-785T is not only associated with changes in serum iodothyronine levels, but also with increased levels of free insulin-like growth factor-I (IGF-I) in two unrelated populations (51). This was substantiated by the association of this haplotype allele with several IGF-I-related endpoints, such as increased muscle strength and muscle mass (51). As IGF-I has a stimulatory effect on D1 expression (55), these higher levels of free IGF-I might be seen as an adaptation to normalize D1 activity in carriers of the D1a-T haplotype allele. Conversely, thyroid hormone stimulates the expression of IGF-binding protein-I (IGFBP-I) in human hepatoma cells (56). A lower activation of thyroid hormone by liver D1 could result in lower levels of IGFBP-1, and thus a higher level of free IGF-I (51), as the majority of IGFBP-1 is produced in the liver.

D2

D2 is important in the production of local T3, but D2 in skeletal muscle also contributes to serum T3 production (48, 57). The above-mentioned association of D2-ORFa-Gly3Asp with the serum T3/T4 ratio also points toward an important role of D2 in serum T3 production (47, 51).

The first polymorphism described in any of the deiodinases was D2-Thr92Ala (46) (Fig. 1). Although this polymorphism does not seem to be associated with serum iodothyronine levels, it has been associated with insulin resistance in three different populations (46, 58, 59). The mechanism behind this association is yet unclear, but it might involve expression of D2 in skeletal muscle and/or in (brown) fat in humans (48). T3 stimulates the transcription of the muscle/fat-specific insulin-sensitive glucose transporter GLUT4 (60). In addition, thyroid hormone augments catecholamine-stimulated lipolysis (61), and a particular inactivating thyroid hormone receptor α mutation results in insulin resistance in mice (62). A decreased D2 activity in insulin-sensitive tissues such as adipose tissue and skeletal muscle, resulting in a decreased availability of local T3, may thus explain the association of D2-Thr92Ala with relative insulin resistance (46, 58, 59). Furthermore, it was recently shown that administration of bile acids to mice can increase energy expenditure, and thereby prevent obesity and insulin resistance via the induction of D2 (63). Alternatively, hypothalamic D2, which regulates the T3 content of brain stem neurons projecting to white adipose tissue, may be involved (64). Although D2 activity does not differ between different cells that are transfected with the D2-92Thr or the D2-92Ala variant (17, 58), a lower activity of D2 has been reported in muscle and thyroid homogenates of carriers of the D2-Ala92 allele (58). This suggests that the consequences of the D2-Thr92Ala polymorphism are caused by linkage with another polymorphism. Haplotype analysis has shown that the D2-Thr92Ala polymorphism and the previously mentioned D2-ORFa-Gly3Asp polymorphism appear on different haplotype alleles (47). So far, there is no evidence of any relationship between the D2-ORFa-Gly3Asp polymorphism and insulin resistance.

Based on the expression pattern of D2, and since D2 is crucial in the regulation of local T3 concentrations, one can speculate about other possible consequences of these and other D2 polymorphisms. Guo et al. studied the relation of the DIO2 gene with mental retardation in iodine-deficient areas of China in a case-control study (n = 96 vs 331 controls) (65). They found a positive association of two intronic D2 polymorphisms (but not of D2-Thr92Ala) with mental retardation in these areas (65), and concluded that genetic variation in D2 may determine the risk of developing mental retardation in an iodine-deficient area, probably by affecting the local amount of T3 available in the brain (65). Appelhof et al. addressed the questions whether genetic variation in the DIO2 gene is a determinant of well-being and neurocognitive functioning in hypothyroid patients on levothyroxine substitution, and whether D2 polymorphisms were associated with a preference for T4/T3 combination therapy over substitution with T4 alone (66). No differences in well-being, neurocognitive functioning or appreciation of T4/T3 combination therapy were detected in these thyroid hormone-replaced hypothyroid patients (66).

D3

Until now, only one polymorphism has been identified in D3 (D3-T1546G), located in the 3′-UTR (17). This polymorphism does not result in altered thyroid hormone levels in healthy individuals. D3 plays an important role in thyroid hormone homeostasis in critical illness and during fetal development, providing protection against thyroid hormone excess (50, 67). Possible effects of this polymorphism on development and under pathophysiological conditions therefore remain to be investigated in future studies. A major obstacle in these studies is that the D3 gene is an imprinted gene, with preferential expression from the paternal allele, as has been studied in a mouse model (43). Therefore, the effects of polymorphisms in the DIO3 gene on thyroid hormone homeostasis depend on the parental origin of the variant allele.

Concluding remarks and future perspectives

Here, we have discussed several polymorphisms in TSHR and the iodothyronine deiodinases that affect serum thyroid hormone levels and/or have effects on thyroid hormone-related physiological endpoints. These polymorphism studies are important for several reasons. First, new insight can be obtained about the physiological function of thyroid hormone pathway genes. The hypothesis regarding a relative decrease in the contribution of D2 to serum T3 production (Fig. 2), based on the different associations of D1 and D2 polymorphisms in younger and elder populations, is an example of this (17, 51), as is the role of D2 activity in the development of insulin resistance (46, 47, 58). Second, genetic variation is important in inter-individual variation in thyroid hormone bioactivity (13). It seems that each individual has a different, genetically determined thyroid function set-point, and that small variations around this set-point, even within the normal range, can have important consequences on, for example, body weight (6). A better selection of subjects, by excluding subjects with autonomous thyroid nodules (68, 69), and standardized (regarding time of day) and perhaps multiple TSH measurements to better define an individual’s set-point (1), would increase the power of such association studies. This raises the possibility of estimating an individual’s set-point based on his/her genetic make-up of thyroid hormone pathway genes. The decision of whether a patient with subclinical changes in thyroid parameters should be treated might then be made on that individual patient’s normal values. In addition, the decision to treat patients with subclinical thyroid disease is based on the risk of these patients developing complications. If the genetic profile makes a patient more vulnerable, then this might be an indication to initiate treatment in an earlier phase.

In addition to peripheral metabolism of thyroid hormone by the deiodinases, transmembrane transport of iodothyronines and expression of thyroid hormone receptors are other key processes in the regulation of thyroid hormone bioactivity. Surprisingly, no studies have yet been published investigating the association of polymorphisms in these transporters and receptors with clinical endpoints. This area of research remains to be explored, and it is likely that exciting new insights will be obtained in the upcoming years.

Acknowledgements

This work was supported by ZonMw Grant: 920-03-146 (RPP).

Table 1

Physiological role in thyroid hormone metabolism, tissue distribution, and substrate preference of the three human iodothyronine selenodeiodinases (D1–D3).

T3, triiodothyronine; T4, thyroxine; rT3, reverse triiodothyronine; BAT, brown adipose tissue.
FunctionPlasma T3 production, rT3 clearanceLocal and plasma T3 productionT3 and T4 clearance, rT3 production
Tissue distributionLiver, kidney, thyroidBrain, pituitary, BAT, thyroid, skeletal muscle, heart, aortic smooth muscle, osteoblastsBrain, skin, placenta, fetal tissues, critically ill liver and skeletal muscle
Substrate preferencerT3 ≫ T4 = T3T4 > rT3T3 > T4
Figure 1
Figure 1

Exonic polymorphisms in the thyroid stimulating hormone receptor (TSHr) and the deiodinases that are described in this study (D1-3). The coding sequence is represented by , the 5′ and 3′ UTR by □, whereas represents an alternatively spliced exon. A UGA codon, coding for selenocysteyl, is depicted by ∇. Finally, selenocysteine insertion sequence elements are indicated by .

Citation: European Journal of Endocrinology eur j endocrinol 155, 5; 10.1530/eje.1.02279

Figure 2
Figure 2

Illustration of the proposed model in which the relative contributionof D2 to serumtriiodothyronine (T3)productiondecreases with an increase in age, based on the different associations of D1 and D2 polymorphisms with serum iodothyronines in one younger (left arrow, 46 years) and two elderly populations (right two arrows, 69 and 77 years respectively). T4, thyroxine.

Citation: European Journal of Endocrinology eur j endocrinol 155, 5; 10.1530/eje.1.02279

References

  • 1

    AndersenS Pedersen KM Bruun NH & Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. Journal of Clinical Endocrinology and Metabolism2002871068–1072.

    • Search Google Scholar
    • Export Citation
  • 2

    HansenPS Brix TH Sorensen TI Kyvik KO & Hegedus L. Major genetic influence on the regulation of the pituitary–thyroid axis: a study of healthy Danish twins. Journal of Clinical Endocrinology and Metabolism2004891181–1187.

    • Search Google Scholar
    • Export Citation
  • 3

    SamollowPB Perez G Kammerer CM Finegold D Zwartjes PW Havill LM Comuzzie AG Mahaney MC Goring HH Blangero J Foley TP & Barmada MM. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. Journal of Clinical Endocrinology and Metabolism2004893276–3284.

    • Search Google Scholar
    • Export Citation
  • 4

    ToftAD. Clinical practice. Subclinical hyperthyroidism. New England Journal of Medicine2001345512–516.

  • 5

    CooperDS. Clinical practice. Subclinical hypothyroidism. New England Journal of Medicine2001345260–265.

  • 6

    KnudsenN Laurberg P Rasmussen LB Bulow I Perrild H Ovesen L & Jorgensen T. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. Journal of Clinical Endocrinology and Metabolism2005904019–4024.

    • Search Google Scholar
    • Export Citation
  • 7

    KrohnK & Paschke R. Somatic mutations in thyroid nodular disease. Molecular Genetics and Metabolism200275202–208.

  • 8

    SunthornthepvarakuiT Gottschalk ME Hayashi Y & Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. New England Journal of Medicine1995332155–160.

    • Search Google Scholar
    • Export Citation
  • 9

    SunthornthepvarakulT Hayashi Y & Refetoff S. Polymorphism of a variant human thyrotropin receptor (hTSHR) gene. Thyroid19944147–149.

  • 10

    GustavssonB Eklof C Westermark K Westermark B & Heldin NE. Functional analysis of a variant of the thyrotropin receptor gene in a family with Graves’ disease. Molecular and Cellular Endocrinology1995111167–173.

    • Search Google Scholar
    • Export Citation
  • 11

    GabrielEM Bergert ER Grant CS Van Heerden JA Thompson GB & Morris JC. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. Journal of Clinical Endocrinology and Metabolism1999843328–3335.

    • Search Google Scholar
    • Export Citation
  • 12

    VillanuevaR Inzerillo AM Tomer Y Barbesino G Meltzer M Concepcion ES Greenberg DA Maclaren N Sun ZS Zhang DM Tucci S & Davies TF. Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid200010791–798.

    • Search Google Scholar
    • Export Citation
  • 13

    SaleMM Akamizu T Howard TD Yokota T Nakao K Mori T Iwasaki H Rich SS Jennings-Gee JE Yamada M & Bowden DW. Association of autoimmune thyroid disease with a microsatellite marker for the thyrotropin receptor gene and CTLA-4 in a Japanese population. Proceedings of the Association of American Physicians1997109453–461.

    • Search Google Scholar
    • Export Citation
  • 14

    HirataniH Bowden DW Ikegami S Shirasawa S Shimizu A Iwatani Y & Akamizu T. Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves’ disease. Journal of Clinical Endocrinology and Metabolism2005902898–2903.

    • Search Google Scholar
    • Export Citation
  • 15

    AkamizuT Sale MM Rich SS Hiratani H Noh JY Kanamoto N Saijo M Miyamoto Y Saito Y Nakao K & Bowden DW. Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients. Thyroid200010851–858.

    • Search Google Scholar
    • Export Citation
  • 16

    De RouxN Misrahi M Chatelain N Gross B & Milgrom E. Microsatellites and PCR primers for genetic studies and genomic sequencing of the human TSH receptor gene. Molecular and Cellular Endocrinology1996117253–256.

    • Search Google Scholar
    • Export Citation
  • 17

    PeetersRP Van Toor H Klootwijk W De Rijke YB Kuiper GG Uitterlinden AG & Visser TJ. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. Journal of Clinical Endocrinology and Metabolism2003882880–2888.

    • Search Google Scholar
    • Export Citation
  • 18

    HansenPS Van Der Deure WM Peeters RP Iachine I Fenger M Sørensen TIA Kyvik KO Visser TJ & Hegedüs L. The impact of a TSH receptor gene polymorphism (Asp727Glu) on thyroid function and size in a healthy Danish twin population. 31st Annual Meeting of the European Thyroid Association Naples Italy 2006 (Abstract P 168).

  • 19

    Van Der DeureWM Uitterlinden AG Pols HAP Peeters RP & Visser TJ. The TSH receptor Asp727Glu polymorphism is associated with higher bone mineral density and bone mineral content. 13th International Thyroid Congress Buenos Aires Argentina 2005 (Abstract O 57).

  • 20

    NogueiraCR Kopp P Arseven OK Santos CL Jameson JL & Medeiros-Neto G. Thyrotropin receptor mutations in hyper-functioning thyroid adenomas from Brazil. Thyroid199991063–1068.

    • Search Google Scholar
    • Export Citation
  • 21

    SykiotisGP Neumann S Georgopoulos NA Sgourou A Papachatzopoulou A Markou KB Kyriazopoulou V Paschke R Vagenakis AG & Papavassiliou AG. Functional significance of the thyrotropin receptor germline polymorphism D727E. Biochemical and Biophysical Research Communications20033011051–1056.

    • Search Google Scholar
    • Export Citation
  • 22

    DechairoBM Zabaneh D Collins J Brand O Dawson GJ Green AP Mackay I Franklyn JA Connell JM Wass JA Wiersinga WM Hegedus L Brix T Robinson BG Hunt PJ Weetman AP Carey AH & Gough SC. Association of the TSHR gene with Graves’ disease: the first disease specific locus. European Journal of Human Genetics2005131223–1230.

    • Search Google Scholar
    • Export Citation
  • 23

    CuddihyRM Bryant WP & Bahn RS. Normal function in vivo of a homozygotic polymorphism in the human thyrotropin receptor. Thyroid19955255–257.

    • Search Google Scholar
    • Export Citation
  • 24

    LoosU Hagner S Bohr UR Bogatkewitsch GS Jakobs KH & Van Koppen CJ. Enhanced cAMP accumulation by the human thyrotropin receptor variant with the Pro52Thr substitution in the extracellular domain. European Journal of Biochemistry199523262–65.

    • Search Google Scholar
    • Export Citation
  • 25

    TonaccheraM & Pinchera A. Thyrotropin receptor polymorphisms and thyroid diseases. Journal of Clinical Endocrinology and Metabolism2000852637–2639.

    • Search Google Scholar
    • Export Citation
  • 26

    CalebiroD De Filippis T Lucchi S Covino C Panigone S Beck-Peccoz P Dunlap D & Persani L. Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Human Molecular Genetics2005142991–3002.

    • Search Google Scholar
    • Export Citation
  • 27

    TomerY Barbesino G Keddache M Greenberg DA & Davies TF. Mapping of a major susceptibility locus for Graves’ disease (GD-1) to chromosome 14q31. Journal of Clinical Endocrinology and Metabolism1997821645–1648.

    • Search Google Scholar
    • Export Citation
  • 28

    BanY Greenberg DA Concepcion ES & Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves’ disease. Thyroid2002121079–1083.

    • Search Google Scholar
    • Export Citation
  • 29

    CuddihyRM Dutton CM & Bahn RS. A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females. Thyroid1995589–95.

    • Search Google Scholar
    • Export Citation
  • 30

    HoSC Goh SS & Khoo DH. Association of Graves’ disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid200313523–528.

    • Search Google Scholar
    • Export Citation
  • 31

    NakabayashiK Matsumi H Bhalla A Bae J Mosselman S Hsu SY & Hsueh AJ. Thyrostimulin a heterodimer of two new human glycoprotein hormone subunits activates the thyroid-stimulating hormone receptor. Journal of Clinical Investigation20021091445–1452.

    • Search Google Scholar
    • Export Citation
  • 32

    MuhlbergT Herrmann K Joba W Kirchberger M Heberling HJ & Heufelder AE. Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population. Journal of Clinical Endocrinology and Metabolism2000852640–2643.

    • Search Google Scholar
    • Export Citation
  • 33

    ChistiakovDA Savost’anov KV Turakulov RI Petunina N Balabolkin MI & Nosikov VV. Further studies of genetic susceptibility to Graves’ disease in a Russian population. Medical Science Monitor2002; 8: CR180–CR184.

    • Search Google Scholar
    • Export Citation
  • 34

    ChistiakovDA. Thyroid-stimulating hormone receptor and its role in Graves’ disease. Molecular Genetics and Metabolism200380377–388.

  • 35

    ChistiakovDA Savost’anov KV & Turakulov RI. Screening of SNPs at 18 positional candidate genes located within the GD-1 locus on chromosome 14q23-q32 for susceptibility to Graves’ disease: a TDT study. Molecular Genetics and Metabolism200483264–270.

    • Search Google Scholar
    • Export Citation
  • 36

    IoannidisJP. Genetic associations: false or true? Trends in Molecular Medicine20039135–138.

  • 37

    BellA Gagnon A Grunder L Parikh SJ Smith TJ & Sorisky A. Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts. American Journal of Physiology. Cell Physiology2000279C335–C340.

    • Search Google Scholar
    • Export Citation
  • 38

    CrisantiP Omri B Hughes E Meduri G Hery C Clauser E Jacquemin C & Saunier B. The expression of thyrotropin receptor in the brain. Endocrinology2001142812–822.

    • Search Google Scholar
    • Export Citation
  • 39

    BahnRS Dutton CM Natt N Joba W Spitzweg C & Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy. Journal of Clinical Endocrinology and Metabolism199883998–1002.

    • Search Google Scholar
    • Export Citation
  • 40

    PaschkeR & Geenen V. Messenger RNA expression for a TSH receptor variant in the thymus of a two-year-old child. Journal of Molecular Medicine199573577–580.

    • Search Google Scholar
    • Export Citation
  • 41

    AbeE Marians RC Yu W Wu XB Ando T Li Y Iqbal J Eldeiry L Rajendren G Blair HC Davies TF & Zaidi M. TSH is a negative regulator of skeletal remodeling. Cell2003115151–162.

    • Search Google Scholar
    • Export Citation
  • 42

    HaraguchiK Shimura H Kawaguchi A Ikeda M Endo T & Onaya T. Effects of thyrotropin on the proliferation and differentiation of cultured rat preadipocytes. Thyroid19999613–619.

    • Search Google Scholar
    • Export Citation
  • 43

    HernandezA Fiering S Martinez E Galton VA & Germain D St. The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology20021434483–4486.

    • Search Google Scholar
    • Export Citation
  • 44

    SchneiderMJ Fiering SN Pallud SE Parlow AF Germain DL St & Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Molecular Endocrinology2001152137–2148.

    • Search Google Scholar
    • Export Citation
  • 45

    BerryMJ Grieco D Taylor BA Maia AL Kieffer JD Beamer W Glover E Poland A & Larsen PR. Physiological and genetic analyses of inbred mouse strains with a type I iodothyronine 5′ deiodinase deficiency. Journal of Clinical Investigation1993921517–1528.

    • Search Google Scholar
    • Export Citation
  • 46

    MentucciaD Proietti-Pannunzi L Tanner K Bacci V Pollin TI Poehlman ET Shuldiner AR & Celi FS. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes200251880–883.

    • Search Google Scholar
    • Export Citation
  • 47

    PeetersRP Van Den Beld AW Attalki H Toor H De Rijke YB Kuiper GG Lamberts SW Janssen JA Uitterlinden AG & Visser TJ. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. American Journal of Physiology. Endocrinology and Metabolism2005289E75–E81.

    • Search Google Scholar
    • Export Citation
  • 48

    BiancoAC Salvatore D Gereben B Berry MJ & Larsen PR. Biochemistry cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews20022338–89.

    • Search Google Scholar
    • Export Citation
  • 49

    LeonardJL & Koehrle J. Intracellular Pathways of Iodothyronine Metabolism Philadelphia PA USA: Lippincot Williams & Wilkins 2000.

  • 50

    PeetersRP Wouters PJ Kaptein E Van Toor H Visser TJ & Van Den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. Journal of Clinical Endocrinology and Metabolism2003883202–3211.

    • Search Google Scholar
    • Export Citation
  • 51

    PeetersRP Van Den Beld AW Van Toor H Uitterlinden AG Janssen JAMJL Lamberts SWF & Visser TJ. A polymorphism in type I deiodinase (D1) is associated with circulating free IGF-I levels and body composition in humans. Journal of Clinical Endocrinology and Metabolism200590256–263.

    • Search Google Scholar
    • Export Citation
  • 52

    SteinsapirJ Bianco AC Buettner C Harney J & Larsen PR. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center. Endocrinology20001411127–1135.

    • Search Google Scholar
    • Export Citation
  • 53

    DondaA & Lemarchand-Beraud T. Aging alters the activity of 5′-deiodinase in the adenohypophysis thyroid gland and liver of the male rat. Endocrinology19891241305–1309.

    • Search Google Scholar
    • Export Citation
  • 54

    GerebenB Kollar A Harney JW & Larsen PR. The mRNA structure has potent regulatory effects on type 2 iodothyronine deiodinase expression. Molecular Endocrinology2002161667–1679.

    • Search Google Scholar
    • Export Citation
  • 55

    HussainMA Schmitz O Jorgensen JO Christiansen JS Weeke J Schmid C & Froesch ER. Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone. European Journal of Endocrinology1996134563–567.

    • Search Google Scholar
    • Export Citation
  • 56

    AngervoM Leinonen P Koistinen R Julkunen M & Seppala M. Tri-iodothyronine and cycloheximide enhance insulin-like growth factor-binding protein-1 gene expression in human hepatoma cells. Journal of Molecular Endocrinology1993107–13.

    • Search Google Scholar
    • Export Citation
  • 57

    MaiaAL Kim BW Huang SA Harney JW & Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Journal of Clinical Investigation20051152524–2533.

    • Search Google Scholar
    • Export Citation
  • 58

    CananiLH Capp C Dora JM Meyer EL Wagner MS Harney JW Larsen PR Gross JL Bianco AC & Maia AL. The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism2005903472–3478.

    • Search Google Scholar
    • Export Citation
  • 59

    PeetersRP Van Den Beld AW Attalki H Toor H Kuiper GG Lamberts SW Janssen JA Uitterlinden AG & Visser TJ. Polymorphisms in the type 2 deiodinase (D2) are associated with serum thyroid parameters and insulin resistance. 76th annual meeting of the American Thyroid Association Vancouver Canada 2004 (P162).

  • 60

    CaslaA Rovira A Wells JA & Dohm GL. Increased glucose transporter (GLUT4) protein expression in hyperthyroidism. Biochemical and Biophysical Research Communications1990171182–188.

    • Search Google Scholar
    • Export Citation
  • 61

    ViguerieN Millet L Avizou S Vidal H Larrouy D & Langin D. Regulation of human adipocyte gene expression by thyroid hormone. Journal of Clinical Endocrinology and Metabolism200287630–634.

    • Search Google Scholar
    • Export Citation
  • 62

    LiuYY Schultz JJ & Brent GA. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. Journal of Biological Chemistry200327838913–38920.

    • Search Google Scholar
    • Export Citation
  • 63

    WatanabeM Houten SM Mataki C Christoffolete MA Kim BW Sato H Messaddeq N Harney JW Ezaki O Kodama T Schoonjans K Bianco AC & Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature2006439484–489.

    • Search Google Scholar
    • Export Citation
  • 64

    RomijnJA & Fliers E. Sympathetic and parasympathetic innervation of adipose tissue: metabolic implications. Current Opinion in Clinical Nutrition and Metabolic Care20058440–444.

    • Search Google Scholar
    • Export Citation
  • 65

    GuoTW Zhang FC Yang MS Gao XC Bian L Duan SW Zheng ZJ Gao JJ Wang H Li RL Feng GY Clair D St & He L. Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China. Journal of Medical Genetics200441585–590.

    • Search Google Scholar
    • Export Citation
  • 66

    AppelhofBC Peeters RP Wiersinga WM Visser TJ Wekking EM Huyser J Schene AH Tijssen JGP Hoogendijk WJG & Fliers E. Polymorphisms in type 2 deiodinase are not associated with well-being neurocognitive functioning and preference for combined T4/T3 therapy. Journal of Clinical Endocrinology and Metabolism2005906296–6299.

    • Search Google Scholar
    • Export Citation
  • 67

    KesterMH Martinez De Mena R Obregon MJ Marinkovic D Howatson A Visser TJ Hume R & Morreale De Escobar G. Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. Journal of Clinical Endocrinology and Metabolism2004893117–3128.

    • Search Google Scholar
    • Export Citation
  • 68

    BerghoutA Wiersinga WM Smits NJ & Touber JL. Interrelationships between age thyroid volume thyroid nodularity and thyroid function in patients with sporadic nontoxic goiter. American Journal of Medicine199089602–608.

    • Search Google Scholar
    • Export Citation
  • 69

    RieuM Bekka S Sambor B Berrod JL & Fombeur JP. Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre. Clinical Endocrinology (Oxf)19933967–71.

    • Search Google Scholar
    • Export Citation

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Figures

  • View in gallery

    Exonic polymorphisms in the thyroid stimulating hormone receptor (TSHr) and the deiodinases that are described in this study (D1-3). The coding sequence is represented by , the 5′ and 3′ UTR by □, whereas represents an alternatively spliced exon. A UGA codon, coding for selenocysteyl, is depicted by ∇. Finally, selenocysteine insertion sequence elements are indicated by .

  • View in gallery

    Illustration of the proposed model in which the relative contributionof D2 to serumtriiodothyronine (T3)productiondecreases with an increase in age, based on the different associations of D1 and D2 polymorphisms with serum iodothyronines in one younger (left arrow, 46 years) and two elderly populations (right two arrows, 69 and 77 years respectively). T4, thyroxine.

References

  • 1

    AndersenS Pedersen KM Bruun NH & Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. Journal of Clinical Endocrinology and Metabolism2002871068–1072.

    • Search Google Scholar
    • Export Citation
  • 2

    HansenPS Brix TH Sorensen TI Kyvik KO & Hegedus L. Major genetic influence on the regulation of the pituitary–thyroid axis: a study of healthy Danish twins. Journal of Clinical Endocrinology and Metabolism2004891181–1187.

    • Search Google Scholar
    • Export Citation
  • 3

    SamollowPB Perez G Kammerer CM Finegold D Zwartjes PW Havill LM Comuzzie AG Mahaney MC Goring HH Blangero J Foley TP & Barmada MM. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. Journal of Clinical Endocrinology and Metabolism2004893276–3284.

    • Search Google Scholar
    • Export Citation
  • 4

    ToftAD. Clinical practice. Subclinical hyperthyroidism. New England Journal of Medicine2001345512–516.

  • 5

    CooperDS. Clinical practice. Subclinical hypothyroidism. New England Journal of Medicine2001345260–265.

  • 6

    KnudsenN Laurberg P Rasmussen LB Bulow I Perrild H Ovesen L & Jorgensen T. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. Journal of Clinical Endocrinology and Metabolism2005904019–4024.

    • Search Google Scholar
    • Export Citation
  • 7

    KrohnK & Paschke R. Somatic mutations in thyroid nodular disease. Molecular Genetics and Metabolism200275202–208.

  • 8

    SunthornthepvarakuiT Gottschalk ME Hayashi Y & Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. New England Journal of Medicine1995332155–160.

    • Search Google Scholar
    • Export Citation
  • 9

    SunthornthepvarakulT Hayashi Y & Refetoff S. Polymorphism of a variant human thyrotropin receptor (hTSHR) gene. Thyroid19944147–149.

  • 10

    GustavssonB Eklof C Westermark K Westermark B & Heldin NE. Functional analysis of a variant of the thyrotropin receptor gene in a family with Graves’ disease. Molecular and Cellular Endocrinology1995111167–173.

    • Search Google Scholar
    • Export Citation
  • 11

    GabrielEM Bergert ER Grant CS Van Heerden JA Thompson GB & Morris JC. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. Journal of Clinical Endocrinology and Metabolism1999843328–3335.

    • Search Google Scholar
    • Export Citation
  • 12

    VillanuevaR Inzerillo AM Tomer Y Barbesino G Meltzer M Concepcion ES Greenberg DA Maclaren N Sun ZS Zhang DM Tucci S & Davies TF. Limited genetic susceptibility to severe Graves’ ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid200010791–798.

    • Search Google Scholar
    • Export Citation
  • 13

    SaleMM Akamizu T Howard TD Yokota T Nakao K Mori T Iwasaki H Rich SS Jennings-Gee JE Yamada M & Bowden DW. Association of autoimmune thyroid disease with a microsatellite marker for the thyrotropin receptor gene and CTLA-4 in a Japanese population. Proceedings of the Association of American Physicians1997109453–461.

    • Search Google Scholar
    • Export Citation
  • 14

    HirataniH Bowden DW Ikegami S Shirasawa S Shimizu A Iwatani Y & Akamizu T. Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves’ disease. Journal of Clinical Endocrinology and Metabolism2005902898–2903.

    • Search Google Scholar
    • Export Citation
  • 15

    AkamizuT Sale MM Rich SS Hiratani H Noh JY Kanamoto N Saijo M Miyamoto Y Saito Y Nakao K & Bowden DW. Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients. Thyroid200010851–858.

    • Search Google Scholar
    • Export Citation
  • 16

    De RouxN Misrahi M Chatelain N Gross B & Milgrom E. Microsatellites and PCR primers for genetic studies and genomic sequencing of the human TSH receptor gene. Molecular and Cellular Endocrinology1996117253–256.

    • Search Google Scholar
    • Export Citation
  • 17

    PeetersRP Van Toor H Klootwijk W De Rijke YB Kuiper GG Uitterlinden AG & Visser TJ. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. Journal of Clinical Endocrinology and Metabolism2003882880–2888.

    • Search Google Scholar
    • Export Citation
  • 18

    HansenPS Van Der Deure WM Peeters RP Iachine I Fenger M Sørensen TIA Kyvik KO Visser TJ & Hegedüs L. The impact of a TSH receptor gene polymorphism (Asp727Glu) on thyroid function and size in a healthy Danish twin population. 31st Annual Meeting of the European Thyroid Association Naples Italy 2006 (Abstract P 168).

  • 19

    Van Der DeureWM Uitterlinden AG Pols HAP Peeters RP & Visser TJ. The TSH receptor Asp727Glu polymorphism is associated with higher bone mineral density and bone mineral content. 13th International Thyroid Congress Buenos Aires Argentina 2005 (Abstract O 57).

  • 20

    NogueiraCR Kopp P Arseven OK Santos CL Jameson JL & Medeiros-Neto G. Thyrotropin receptor mutations in hyper-functioning thyroid adenomas from Brazil. Thyroid199991063–1068.

    • Search Google Scholar
    • Export Citation
  • 21

    SykiotisGP Neumann S Georgopoulos NA Sgourou A Papachatzopoulou A Markou KB Kyriazopoulou V Paschke R Vagenakis AG & Papavassiliou AG. Functional significance of the thyrotropin receptor germline polymorphism D727E. Biochemical and Biophysical Research Communications20033011051–1056.

    • Search Google Scholar
    • Export Citation
  • 22

    DechairoBM Zabaneh D Collins J Brand O Dawson GJ Green AP Mackay I Franklyn JA Connell JM Wass JA Wiersinga WM Hegedus L Brix T Robinson BG Hunt PJ Weetman AP Carey AH & Gough SC. Association of the TSHR gene with Graves’ disease: the first disease specific locus. European Journal of Human Genetics2005131223–1230.

    • Search Google Scholar
    • Export Citation
  • 23

    CuddihyRM Bryant WP & Bahn RS. Normal function in vivo of a homozygotic polymorphism in the human thyrotropin receptor. Thyroid19955255–257.

    • Search Google Scholar
    • Export Citation
  • 24

    LoosU Hagner S Bohr UR Bogatkewitsch GS Jakobs KH & Van Koppen CJ. Enhanced cAMP accumulation by the human thyrotropin receptor variant with the Pro52Thr substitution in the extracellular domain. European Journal of Biochemistry199523262–65.

    • Search Google Scholar
    • Export Citation
  • 25

    TonaccheraM & Pinchera A. Thyrotropin receptor polymorphisms and thyroid diseases. Journal of Clinical Endocrinology and Metabolism2000852637–2639.

    • Search Google Scholar
    • Export Citation
  • 26

    CalebiroD De Filippis T Lucchi S Covino C Panigone S Beck-Peccoz P Dunlap D & Persani L. Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Human Molecular Genetics2005142991–3002.

    • Search Google Scholar
    • Export Citation
  • 27

    TomerY Barbesino G Keddache M Greenberg DA & Davies TF. Mapping of a major susceptibility locus for Graves’ disease (GD-1) to chromosome 14q31. Journal of Clinical Endocrinology and Metabolism1997821645–1648.

    • Search Google Scholar
    • Export Citation
  • 28

    BanY Greenberg DA Concepcion ES & Tomer Y. A germline single nucleotide polymorphism at the intracellular domain of the human thyrotropin receptor does not have a major effect on the development of Graves’ disease. Thyroid2002121079–1083.

    • Search Google Scholar
    • Export Citation
  • 29

    CuddihyRM Dutton CM & Bahn RS. A polymorphism in the extracellular domain of the thyrotropin receptor is highly associated with autoimmune thyroid disease in females. Thyroid1995589–95.

    • Search Google Scholar
    • Export Citation
  • 30

    HoSC Goh SS & Khoo DH. Association of Graves’ disease with intragenic polymorphism of the thyrotropin receptor gene in a cohort of Singapore patients of multi-ethnic origins. Thyroid200313523–528.

    • Search Google Scholar
    • Export Citation
  • 31

    NakabayashiK Matsumi H Bhalla A Bae J Mosselman S Hsu SY & Hsueh AJ. Thyrostimulin a heterodimer of two new human glycoprotein hormone subunits activates the thyroid-stimulating hormone receptor. Journal of Clinical Investigation20021091445–1452.

    • Search Google Scholar
    • Export Citation
  • 32

    MuhlbergT Herrmann K Joba W Kirchberger M Heberling HJ & Heufelder AE. Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population. Journal of Clinical Endocrinology and Metabolism2000852640–2643.

    • Search Google Scholar
    • Export Citation
  • 33

    ChistiakovDA Savost’anov KV Turakulov RI Petunina N Balabolkin MI & Nosikov VV. Further studies of genetic susceptibility to Graves’ disease in a Russian population. Medical Science Monitor2002; 8: CR180–CR184.

    • Search Google Scholar
    • Export Citation
  • 34

    ChistiakovDA. Thyroid-stimulating hormone receptor and its role in Graves’ disease. Molecular Genetics and Metabolism200380377–388.

  • 35

    ChistiakovDA Savost’anov KV & Turakulov RI. Screening of SNPs at 18 positional candidate genes located within the GD-1 locus on chromosome 14q23-q32 for susceptibility to Graves’ disease: a TDT study. Molecular Genetics and Metabolism200483264–270.

    • Search Google Scholar
    • Export Citation
  • 36

    IoannidisJP. Genetic associations: false or true? Trends in Molecular Medicine20039135–138.

  • 37

    BellA Gagnon A Grunder L Parikh SJ Smith TJ & Sorisky A. Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts. American Journal of Physiology. Cell Physiology2000279C335–C340.

    • Search Google Scholar
    • Export Citation
  • 38

    CrisantiP Omri B Hughes E Meduri G Hery C Clauser E Jacquemin C & Saunier B. The expression of thyrotropin receptor in the brain. Endocrinology2001142812–822.

    • Search Google Scholar
    • Export Citation
  • 39

    BahnRS Dutton CM Natt N Joba W Spitzweg C & Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy. Journal of Clinical Endocrinology and Metabolism199883998–1002.

    • Search Google Scholar
    • Export Citation
  • 40

    PaschkeR & Geenen V. Messenger RNA expression for a TSH receptor variant in the thymus of a two-year-old child. Journal of Molecular Medicine199573577–580.

    • Search Google Scholar
    • Export Citation
  • 41

    AbeE Marians RC Yu W Wu XB Ando T Li Y Iqbal J Eldeiry L Rajendren G Blair HC Davies TF & Zaidi M. TSH is a negative regulator of skeletal remodeling. Cell2003115151–162.

    • Search Google Scholar
    • Export Citation
  • 42

    HaraguchiK Shimura H Kawaguchi A Ikeda M Endo T & Onaya T. Effects of thyrotropin on the proliferation and differentiation of cultured rat preadipocytes. Thyroid19999613–619.

    • Search Google Scholar
    • Export Citation
  • 43

    HernandezA Fiering S Martinez E Galton VA & Germain D St. The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts. Endocrinology20021434483–4486.

    • Search Google Scholar
    • Export Citation
  • 44

    SchneiderMJ Fiering SN Pallud SE Parlow AF Germain DL St & Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Molecular Endocrinology2001152137–2148.

    • Search Google Scholar
    • Export Citation
  • 45

    BerryMJ Grieco D Taylor BA Maia AL Kieffer JD Beamer W Glover E Poland A & Larsen PR. Physiological and genetic analyses of inbred mouse strains with a type I iodothyronine 5′ deiodinase deficiency. Journal of Clinical Investigation1993921517–1528.

    • Search Google Scholar
    • Export Citation
  • 46

    MentucciaD Proietti-Pannunzi L Tanner K Bacci V Pollin TI Poehlman ET Shuldiner AR & Celi FS. Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor. Diabetes200251880–883.

    • Search Google Scholar
    • Export Citation
  • 47

    PeetersRP Van Den Beld AW Attalki H Toor H De Rijke YB Kuiper GG Lamberts SW Janssen JA Uitterlinden AG & Visser TJ. A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. American Journal of Physiology. Endocrinology and Metabolism2005289E75–E81.

    • Search Google Scholar
    • Export Citation
  • 48

    BiancoAC Salvatore D Gereben B Berry MJ & Larsen PR. Biochemistry cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews20022338–89.

    • Search Google Scholar
    • Export Citation
  • 49

    LeonardJL & Koehrle J. Intracellular Pathways of Iodothyronine Metabolism Philadelphia PA USA: Lippincot Williams & Wilkins 2000.

  • 50

    PeetersRP Wouters PJ Kaptein E Van Toor H Visser TJ & Van Den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. Journal of Clinical Endocrinology and Metabolism2003883202–3211.

    • Search Google Scholar
    • Export Citation
  • 51

    PeetersRP Van Den Beld AW Van Toor H Uitterlinden AG Janssen JAMJL Lamberts SWF & Visser TJ. A polymorphism in type I deiodinase (D1) is associated with circulating free IGF-I levels and body composition in humans. Journal of Clinical Endocrinology and Metabolism200590256–263.

    • Search Google Scholar
    • Export Citation
  • 52

    SteinsapirJ Bianco AC Buettner C Harney J & Larsen PR. Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme’s active center. Endocrinology20001411127–1135.

    • Search Google Scholar
    • Export Citation
  • 53

    DondaA & Lemarchand-Beraud T. Aging alters the activity of 5′-deiodinase in the adenohypophysis thyroid gland and liver of the male rat. Endocrinology19891241305–1309.

    • Search Google Scholar
    • Export Citation
  • 54

    GerebenB Kollar A Harney JW & Larsen PR. The mRNA structure has potent regulatory effects on type 2 iodothyronine deiodinase expression. Molecular Endocrinology2002161667–1679.

    • Search Google Scholar
    • Export Citation
  • 55

    HussainMA Schmitz O Jorgensen JO Christiansen JS Weeke J Schmid C & Froesch ER. Insulin-like growth factor I alters peripheral thyroid hormone metabolism in humans: comparison with growth hormone. European Journal of Endocrinology1996134563–567.

    • Search Google Scholar
    • Export Citation
  • 56

    AngervoM Leinonen P Koistinen R Julkunen M & Seppala M. Tri-iodothyronine and cycloheximide enhance insulin-like growth factor-binding protein-1 gene expression in human hepatoma cells. Journal of Molecular Endocrinology1993107–13.

    • Search Google Scholar
    • Export Citation
  • 57

    MaiaAL Kim BW Huang SA Harney JW & Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. Journal of Clinical Investigation20051152524–2533.

    • Search Google Scholar
    • Export Citation
  • 58

    CananiLH Capp C Dora JM Meyer EL Wagner MS Harney JW Larsen PR Gross JL Bianco AC & Maia AL. The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with type 2 diabetes mellitus. Journal of Clinical Endocrinology and Metabolism2005903472–3478.

    • Search Google Scholar
    • Export Citation
  • 59

    PeetersRP Van Den Beld AW Attalki H Toor H Kuiper GG Lamberts SW Janssen JA Uitterlinden AG & Visser TJ. Polymorphisms in the type 2 deiodinase (D2) are associated with serum thyroid parameters and insulin resistance. 76th annual meeting of the American Thyroid Association Vancouver Canada 2004 (P162).

  • 60

    CaslaA Rovira A Wells JA & Dohm GL. Increased glucose transporter (GLUT4) protein expression in hyperthyroidism. Biochemical and Biophysical Research Communications1990171182–188.

    • Search Google Scholar
    • Export Citation
  • 61

    ViguerieN Millet L Avizou S Vidal H Larrouy D & Langin D. Regulation of human adipocyte gene expression by thyroid hormone. Journal of Clinical Endocrinology and Metabolism200287630–634.

    • Search Google Scholar
    • Export Citation
  • 62

    LiuYY Schultz JJ & Brent GA. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. Journal of Biological Chemistry200327838913–38920.

    • Search Google Scholar
    • Export Citation
  • 63

    WatanabeM Houten SM Mataki C Christoffolete MA Kim BW Sato H Messaddeq N Harney JW Ezaki O Kodama T Schoonjans K Bianco AC & Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature2006439484–489.

    • Search Google Scholar
    • Export Citation
  • 64

    RomijnJA & Fliers E. Sympathetic and parasympathetic innervation of adipose tissue: metabolic implications. Current Opinion in Clinical Nutrition and Metabolic Care20058440–444.

    • Search Google Scholar
    • Export Citation
  • 65

    GuoTW Zhang FC Yang MS Gao XC Bian L Duan SW Zheng ZJ Gao JJ Wang H Li RL Feng GY Clair D St & He L. Positive association of the DIO2 (deiodinase type 2) gene with mental retardation in the iodine-deficient areas of China. Journal of Medical Genetics200441585–590.

    • Search Google Scholar
    • Export Citation
  • 66

    AppelhofBC Peeters RP Wiersinga WM Visser TJ Wekking EM Huyser J Schene AH Tijssen JGP Hoogendijk WJG & Fliers E. Polymorphisms in type 2 deiodinase are not associated with well-being neurocognitive functioning and preference for combined T4/T3 therapy. Journal of Clinical Endocrinology and Metabolism2005906296–6299.

    • Search Google Scholar
    • Export Citation
  • 67

    KesterMH Martinez De Mena R Obregon MJ Marinkovic D Howatson A Visser TJ Hume R & Morreale De Escobar G. Iodothyronine levels in the human developing brain: major regulatory roles of iodothyronine deiodinases in different areas. Journal of Clinical Endocrinology and Metabolism2004893117–3128.

    • Search Google Scholar
    • Export Citation
  • 68

    BerghoutA Wiersinga WM Smits NJ & Touber JL. Interrelationships between age thyroid volume thyroid nodularity and thyroid function in patients with sporadic nontoxic goiter. American Journal of Medicine199089602–608.

    • Search Google Scholar
    • Export Citation
  • 69

    RieuM Bekka S Sambor B Berrod JL & Fombeur JP. Prevalence of subclinical hyperthyroidism and relationship between thyroid hormonal status and thyroid ultrasonographic parameters in patients with non-toxic nodular goitre. Clinical Endocrinology (Oxf)19933967–71.

    • Search Google Scholar
    • Export Citation

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