A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

Abstract

Type II deiodinase (D2) is important in the regulation of local thyroid hormone bioactivity in certain tissues. D2 in skeletal muscle may also play a role in serum triiodothyronine (T 3) production. In this study, we identified a polymorphism in the 5Ј-UTR of the D2 gene (D2-ORFa-Gly3Asp). We investigated the association of D2-ORFa-Gly3Asp, and of the previously identified D2-Thr92Ala polymorphism, with serum iodothyronine levels. D2-ORFa-Gly3Asp was identified by sequencing the 5Ј-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 Ϯ 12.2 yr) and 349 ambulant elderly men (age 77.7 Ϯ 3.5 yr) and related to serum iodothyronine and TSH levels. D2-ORFa-Asp 3 had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T 4; Gly/Gly vs. Gly/Asp vs. Asp/Asp ϭ 7.06 Ϯ 0.14 vs. 6.74 Ϯ 0.15 vs. 6.29 Ϯ 0.27 g/dl, P ϭ 0.01), free T 4 (1.22 Ϯ 0.02 vs. 1.16 Ϯ 0.02 vs. 1.06 Ϯ 0.04 ng/dl, P ϭ 0.001), reverse T 3 (P ϭ 0.01), and T3/T4 ratio (P ϭ 0.002) in a dose-dependent manner, but not with serum T 3 (P ϭ 0.59). In elderly men, D2-ORFa-Asp 3 had a similar frequency but was not associated with serum iodothyronine levels. This new polymorphism in the 5Ј-UTR of D2 is associated with iodothyronine levels in blood donors but not in elderly men. We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T 3 production.iodothyronines; open reading frame; population; association THYROID HORMONE IS ESSENTIAL for growth, development, and regulation of energy metabolism (14). It stimulates metabolic rate by increasing ATP turnover and by regulating the expression of uncoupling proteins in the mitochondria of fat and skeletal muscle (26,33). 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 triiodothyronine (T 3 ), is mainly regulated by the three different selenodeiodinases (D1-D3) (2, 15). Tissue distribution and enzymatic activity of the three deiodinases are highly specific, and they all play a different physiological role. D2 is present in brain, pituitary, thyroid, brown adipose tissue, skeletal muscle, and aortic smooth muscle cells in humans (2,6,15,17,20,30,31). It converts thyroxine (T 4 ) to T 3 by outer-ring deiodination, and it is important in the regulation of local thyroid hormone bioactivity in D2-expressing tissues. D2 in skeletal muscle may also contribute to serum T 3 production (2, 30).The mRNA of the D2 gene is unusually long (6 -7 kb) compared with the other two selenodeiodinases, containing long 5Ј-and 3Ј-untranslated regions (UTRs) (1, 3-5). The 5Ј-UTR of the D2 mRNA is ϳ700 nt long and has an inhibitory effect on D2 translation. It causes a fivefold reduction in D2 activity in HEK-293 cells (9). This 5Ј-UTR contains three short open reading frames [sORFs (1, 4, 5); Fig. 1]. The most ...

The Thr92Ala 5′ Type 2 Deiodinase Gene Polymorphism Is Associated with a Delayed Triiodothyronine Secretion in Response to the Thyrotropin-Releasing Hormone–Stimulation Test: A Pharmacogenomic Study

“…The effects of the Thr92Ala polymorphism on circulating levels of thyroid hormones are somewhat controversial: Peeters et al found significantly lower plasma TSH levels and TSH/T4 ratios in heterozygous subjects, but no association with circulating iodothyronine levels (13) and confirmed this finding in a follow-up study (12) and also in elderly subjects (12,13,22). Recently, however, Torlontano et al demonstrated that athyreotic patients homozygous for the Ala variant require higher doses of T4 replacement therapy to achieve nearsuppression of serum TSH (11).…”

“…The results are, nonetheless, conflicting (12) and the clinical data are mostly derived from secondary analyses of cross-sectional studies aimed to analyze other endpoints.…”

“…The common Thr92Ala D2 polymorphism (7) has been associated with traits of impaired thyroid hormone action at various end-organ targets (7-10), the hypothalamic-pituitary level (11), and in circulating levels of thyroid hormones (12). Nonetheless, results are conflicting (13)(14)(15)(16) and the data refer to steady-state serum thyroid hormone levels.…”

Heredity and lifestyle in the determination of between-subject variation in thyroid hormone levels in euthyroid men

“…Twin studies demonstrate a moderately strong genetic influence (7,8,9,10,11). In recent years, several of the genes involved in this regulation have been identified, with common genetic variation in phosphodiesterase 8B (PDE8B), TSH receptor (TSHR), deiodinase 1 (DIO1), and capping protein muscle Z-line beta (CAPZB) being associated with circulating THs (12,13,14,15,16,17,18,19,20,21,22). Besides, some of these single-nucleotide polymorphisms (SNPs) in the TH pathway have also been associated with clinical characteristics such as lean mass, bone density, hypertension, and insulin resistance (23,24,25,26,27,28).…”

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

“…The Ala92 allele had a frequency of 45%, which is similar to previous studies in Caucasians. (33,31) The characteristics of the three genotype subgroups are given in Table 2. The three groups were comparable with respect to age, gender, estrogen state (including ages at menarche and menopause), and BMI.…”