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.


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).


RESULTS
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.
Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
Helena Gásdal
HG
Sørensen
Wendy M
WM
van der Deure
Pia Skov
PS
Hansen
Robin P
RP
Peeters
Monique M B
MM
Breteler
Kirsten Ohm
KO
Kyvik
Thorkild I A
TI
Sørensen
Laszlo
L
Hegedüs
Theo J
TJ
Visser
D000328:Adult; D000368:Aged; D003718:Denmark; D005260:Female; D006801:Humans; D008297:Male; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood
D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D013963:Thyroid Hormones; D013972:Thyrotropin