m_ob
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This study showing the strong relationship between thyroid hormone levels and single nucleotide polymorphisms, or "snips." I'm sure all of you have heard of snps, but it can be hard to relate these small mutations to anything majorly relevant to health. Well I came across a study done doing just that. This study shows just how important these snps are to how well we feel and how we function.
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.
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 (4–6). 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.
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
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 (1–3). 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.
References
Top
Abstract
Introduction
Polymorphisms in the TSH...
Polymorphisms in the...
Concluding remarks and future...
References
1. Andersen S, 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 Metabolism 2002 87 1068–1072.[Abstract/Free Full Text]
2. Hansen PS, 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 Metabolism 2004 89 1181–1187.[Abstract/Free Full Text]
3. Samollow PB, 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 Metabolism 2004 89 3276–3284.[Abstract/Free Full Text]
4. Toft AD. Clinical practice. Subclinical hyperthyroidism. New England Journal of Medicine 2001 345 512–516.[Free Full Text]
5. Cooper DS. Clinical practice. Subclinical hypothyroidism. New England Journal of Medicine 2001 345 260–265.[Free Full Text]
6. Knudsen N, 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 Metabolism 2005 90 4019–4024.[Abstract/Free Full Text]
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17. Peeters RP, 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 Metabolism 2003 88 2880–2888.[Abstract/Free Full Text]
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32. Muhlberg T, 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 Metabolism 2000 85 2640–2643.[Abstract/Free Full Text]
33. Chistiakov DA, 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 Monitor 2002; 8: CR180–CR184.
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35. Chistiakov DA, 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 Metabolism 2004 83 264–270.[CrossRef][Web of Science][Medline]
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38. Crisanti P, Omri B, Hughes E, Meduri G, Hery C, Clauser E, Jacquemin C & Saunier B. The expression of thyrotropin receptor in the brain. Endocrinology 2001 142 812–822.[Abstract/Free Full Text]
39. Bahn RS, 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 Metabolism 1998 83 998–1002.[Abstract/Free Full Text]
40. Paschke R & Geenen V. Messenger RNA expression for a TSH receptor variant in the thymus of a two-year-old child. Journal of Molecular Medicine 1995 73 577–580.[Web of Science][Medline]
41. Abe E, 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. Cell 2003 115 151–162.[CrossRef][Web of Science][Medline]
42. Haraguchi K, Shimura H, Kawaguchi A, Ikeda M, Endo T & Onaya T. Effects of thyrotropin on the proliferation and differentiation of cultured rat preadipocytes. Thyroid 1999 9 613–619.[Web of Science][Medline]
43. Hernandez A, 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. Endocrinology 2002 143 4483–4486.[Abstract]
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47. Peeters RP, 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 Metabolism 2005 289 E75–E81.[Abstract/Free Full Text]
48. Bianco AC, Salvatore D, Gereben B, Berry MJ & Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocrine Reviews 2002 23 38–89.[Abstract/Free Full Text]
49. Leonard JL & Koehrle J. Intracellular Pathways of Iodothyronine Metabolism Philadelphia, PA, USA: Lippincot Williams & Wilkins, 2000.
50. Peeters RP, 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 Metabolism 2003 88 3202–3211.[Abstract/Free Full Text]
51. Peeters RP, 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 Metabolism 2005 90 256–263.[Abstract/Free Full Text]
52. Steinsapir J, 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. Endocrinology 2000 141 1127–1135.[Abstract/Free Full Text]
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54. Gereben B, Kollar A, Harney JW & Larsen PR. The mRNA structure has potent regulatory effects on type 2 iodothyronine deiodinase expression. Molecular Endocrinology 2002 16 1667–1679.[Abstract/Free Full Text]
55. Hussain MA, 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 Endocrinology 1996 134 563–567.[Abstract/Free Full Text]
56. Angervo M, 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 Endocrinology 1993 10 7–13.[Abstract/Free Full Text]
57. Maia AL, 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 Investigation 2005 115 2524–2533.[CrossRef][Web of Science][Medline]
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59. Peeters RP, 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).
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62. Liu YY, 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 Chemistry 2003 278 38913–38920.[Abstract/Free Full Text]
63. Watanabe M, 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. Nature 2006 439 484–489.[CrossRef][Medline]
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--------------------------------------------------------------------------------
Received 9 June 2006
Accepted 29 August 2006
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.
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 (4–6). 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.
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
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 (1–3). 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.
References
Top
Abstract
Introduction
Polymorphisms in the TSH...
Polymorphisms in the...
Concluding remarks and future...
References
1. Andersen S, 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 Metabolism 2002 87 1068–1072.[Abstract/Free Full Text]
2. Hansen PS, 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 Metabolism 2004 89 1181–1187.[Abstract/Free Full Text]
3. Samollow PB, 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 Metabolism 2004 89 3276–3284.[Abstract/Free Full Text]
4. Toft AD. Clinical practice. Subclinical hyperthyroidism. New England Journal of Medicine 2001 345 512–516.[Free Full Text]
5. Cooper DS. Clinical practice. Subclinical hypothyroidism. New England Journal of Medicine 2001 345 260–265.[Free Full Text]
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Received 9 June 2006
Accepted 29 August 2006
