Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes.

OBJECTIVE Genetic factors exert considerable influence on thyroid function variables. Single nucleotide polymorphisms (SNPs) in thyroid hormone pathway genes have been associated with serum thyroid parameters implying small alterations in the hypothalamus-pituitary-thyroid axis. However, little is known about SNPs in the THRA (17q11.2) and THRB (3p24.2) genes. The aim of this study was to map THRA and THRB for the occurrence and frequencies of SNPs and relate these to thyroid parameters. DESIGN AND METHODS SNPs were identified by sequencing all THRA and THRB exons and flanking regions in 52 randomly selected subjects. SNPs were genotyped in 1116 healthy Danish twins by TaqMan assays and related to thyroid parameters. One SNP in THRB was additionally genotyped in the elderly population of the Rotterdam Scan Study (n = 940). MAIN OUTCOME 15 SNPs (7 novel) in THRA and THRB were identified. Two SNPs in the 3' untranslated region of THRA were genotyped: a novel SNP (2390A/G) and 1895C/A (rs12939700). In THRB, a synonymous (735C/T; rs3752874) and an intronic SNP (in9-G/A; rs13063628) were genotyped. No associations between SNPs and thyroid hormone levels (total and free 3,3',5-triiodo-L-thyronine [T3] and thyroxine, reverse T3) were found. THRB-in9-G/A was significantly associated with higher serum thyroid stimulating hormone (TSH) (p(lnTSH) = 0.01) in the Danish twins, but not in subjects of the Rotterdam Scan Study, although it showed a similar trend. CONCLUSIONS Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins.

[1]  S. Bandinelli,et al.  Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. , 2008, American journal of human genetics.

[2]  K. Schousboe,et al.  Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome? , 2007, Diabetologia.

[3]  L. Hegedüs,et al.  The impact of a TSH receptor gene polymorphism on thyroid‐related phenotypes in a healthy Danish twin population , 2007, Clinical endocrinology.

[4]  T. Visser,et al.  Genetic variation in thyroid hormone transporters. , 2007, Best practice & research. Clinical endocrinology & metabolism.

[5]  L. Hegedüs,et al.  Genetic and environmental interrelations between measurements of thyroid function in a healthy Danish twin population. , 2007, American journal of physiology. Endocrinology and metabolism.

[6]  A. Hofman,et al.  The association of polymorphisms in the type 1 and 2 deiodinase genes with circulating thyroid hormone parameters and atrophy of the medial temporal lobe. , 2007, The Journal of clinical endocrinology and metabolism.

[7]  P. Beck‐Peccoz,et al.  Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis. , 2006, Best practice & research. Clinical endocrinology & metabolism.

[8]  M. Weissel.  Disturbances of thyroid function in the elderly , 2006, Wiener klinische Wochenschrift.

[9]  J. Bernal,et al.  Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. , 2005, Genes & development.

[10]  A. Uitterlinden,et al.  A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters. , 2005, American journal of physiology. Endocrinology and metabolism.

[11]  Sheue-yann Cheng,et al.  Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance , 2005, Trends in Endocrinology & Metabolism.

[12]  R. Marcos,et al.  Thyroid Cancer Susceptibility and THRA1 and BAT-40 Repeats Polymorphisms , 2005, Cancer Epidemiology Biomarkers & Prevention.

[13]  J. Blangero,et al.  Genetic and environmental influences on thyroid hormone variation in Mexican Americans. , 2004, The Journal of clinical endocrinology and metabolism.

[14]  Kirsten Ohm Kyvik,et al.  Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins. , 2004, The Journal of clinical endocrinology and metabolism.

[15]  C. Ohlsson,et al.  Retardation of post‐natal development caused by a negatively acting thyroid hormone receptor α1 , 2002, The EMBO journal.

[16]  N. Rampino,et al.  Expansion of microsatellite in the thyroid hormone receptor-alpha1 gene linked to increased receptor expression and less aggressive thyroid cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[17]  P. Laurberg,et al.  Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. , 2002, The Journal of clinical endocrinology and metabolism.

[18]  L. Peltonen,et al.  Scanning of estrogen receptor alpha (ERalpha) and thyroid hormone receptor alpha (TRalpha) genes in patients with psychiatric diseases: four missense mutations identified in ERalpha gene. , 2001, American journal of medical genetics.

[19]  F. Wondisford,et al.  Critical role for thyroid hormone receptor beta2 in the regulation of paraventricular thyrotropin-releasing hormone neurons. , 2001, The Journal of clinical investigation.

[20]  G. Williams,et al.  Cloning and Characterization of Two Novel Thyroid Hormone Receptor β Isoforms , 2000, Molecular and Cellular Biology.

[21]  M. Breteler.  Vascular Involvement in Cognitive Decline and Dementia: Epidemiologic Evidence from the Rotterdam Study and the Rotterdam Scan Study , 2000, Annals of the New York Academy of Sciences.

[22]  M. Crawford,et al.  Genetic and environmental components of thyroxine variation in Mennonites from Kansas and Nebraska. , 1998, Human biology.

[23]  C. Franceschi,et al.  The aging thyroid. , 1995, Endocrine reviews.

[24]  P. Beck‐Peccoz,et al.  Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone. Identification of thirteen novel mutations in the thyroid hormone receptor beta gene. , 1994, The Journal of clinical investigation.

[25]  V. Laudet,et al.  Genomic organization of the human thyroid hormone receptor α (c-erbA-1) gene , 1991 .

[26]  L. Degroot,et al.  Structural analysis of human thyroid hormone receptor β gene , 1990, Molecular and Cellular Endocrinology.

[27]  A. Meikle,et al.  Hereditary and environmental influences on the variation of thyroid hormones in normal male twins. , 1988, The Journal of clinical endocrinology and metabolism.

[28]  T. Visser,et al.  Radioimmunoassay of reverse tri-iodothyronine. , 1977, The Journal of endocrinology.

[29]  A. Uitterlinden,et al.  A polymorphism in type I deiodinase is associated with circulating free insulin-like growth factor I levels and body composition in humans. , 2005, The Journal of clinical endocrinology and metabolism.

[30]  A. Uitterlinden,et al.  Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. , 2003, The Journal of clinical endocrinology and metabolism.

[31]  M. Lazar,et al.  The mechanism of action of thyroid hormones. , 2000, Annual review of physiology.