A Common Variation in Deiodinase 1 Gene DIO1 Is Associated with the Relative Levels of Free Thyroxine and Triiodothyronine (original) (raw)
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American Journal of Physiology-Endocrinology and Metabolism, 2005
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 (T3) production. In this study, we identified a polymorphism in the 5′-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 5′-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 ± 12.2 yr) and 349 ambulant elderly men (age 77.7 ± 3.5 yr) and related to serum iodothyronine and TSH levels. D2-ORFa-Asp3had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T4; Gly/Gly vs. Gly/Asp vs. Asp/Asp = 7.06 ± 0.14 vs. 6.74 ± 0.15 vs. 6.29 ± 0.27 μg/dl, P = 0.01), free T4(1.22 ± 0.02 vs. 1.16 ± 0.02 vs. 1.06 ± 0.04 ng/dl, P = 0.001...
Turkish journal of pharmaceutical sciences, 2022
Objectives: Levothyroxine (LT4) is a commonly used treatment for hypothyroidism. Deiodinase enzymes control the metabolism and homeostasis of thyroid hormones (THs). Deiodinase type 3 gene (DIO3) encodes deiodinase type 3 enzyme (D3), and the genetic polymorphisms of this gene could affect the levels of THs and the response to LT4 treatment. This study aimed to investigate the single-nucleotide polymorphism (SNP), rs1190716; C > T, of DIO3 as a candidate genetic variant that might affect the clinical response to LT4 treatment. Materials and Methods: Two hundred Iraqi hypothyroid female patients aged 40 years were enrolled in this cross-sectional study. All of them were already on the LT4 treatment for at least 4 months. THs [thyroxin (T4), triiodothyronine (T3), reverse triiodothyronine (rT3), and diiodothyronine (T2)] were estimated. An allele-specific polymerase chain reaction technique was performed to detect the rs1190716; C > T SNP. Results: The genotypes distribution of rs1190716; C > T SNP was 10 (4.5%) for the wild type (CC), 50 (22.7%) for the heterozygous mutant type (TC), and 160 (72.7%) for the homozygous mutant type (TT). The patients were divided into three groups according to their genotypes. Significant differences were found in the T4, T3, and T2 levels among the patients (p=0.019, p=0.039, p=0.032, respectively). Conclusion: The rs1190716; C > T SNP could affect the activity of the D3 enzyme and the metabolic homeostasis of the THs; therefore rs1190716; C > T SNP could have an impact on the therapeutic response to LT4 in Iraqi female patients with primary hypothyroidism. Regarding DIO3 gene, this is a novel finding; hence, further studies are needed to confirm it.
Clinical Endocrinology, 2009
Introduction Genetic factors have a considerable influence on serum thyroid hormone levels. The C785T and A1814G polymorphisms, located in the 3 ′ untranslated region of the type 1 deiodinase (D1) gene have been associated with serum FT4 and rT3 levels. Objective In healthy Danish twins, we examined the association of these polymorphisms with serum thyroid hormone levels and determined the proportion of genetic influence explained by these variants. We analysed the underlying functional mechanism by performing mRNA stability measurements and analysed the effect of these variants on D1 activity. Methods Serum thyroid measurements and genotypes of the D1-C785T and D1-A1814G polymorphisms were determined in 1192 twins. Structural equation modelling was used to determine heritability estimates. Functional analyses were carried out in D1transfected JEG3 cells. Results Carriers of the D1-785T allele had 3·8% higher FT4 and 14·3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio. This polymorphism explained 0·87% and 1·79%, respectively, of the variation in serum FT4 and rT3. The D1-A1814G polymorphism was not associated with serum thyroid hormone levels. No differences in D1 mRNA decay rate or D1 activity were observed between wild-type D1 and the two variants. Conclusion The D1-C785T polymorphism is consistently and significantly associated with serum thyroid hormone levels. However, the proportion of genetic influence explained by this particular polymorphism is small. No effect of the polymorphism on D1 mRNA decay rate or D1 activity was observed. The underlying functional mechanism needs to be elucidated.
2010
Background: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland. Methods: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. Results: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 AE 2.67 vs. 21.07 AE 2.86 ng/dL, p ¼ 0.029). Thr/Ala subjects showed an intermediate response.
DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients
The Journal of Clinical Endocrinology & Metabolism
Context:A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions.Objectives:To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis.Design:We compared the presurgical hormonal status of thyroidectomized LT4-treated patients who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients. We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models.Subjects and methods:A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohist...
Revista Romana de Medicina de Laborator, 2019
The aim of this study was to evaluate the prevalence of the Iodothyronine Deiodinase 2 gene Thr92Ala polymorphism in children from West of Romania with congenital hypothyroidism (CH) and association with TSH levels in response to levothyroxine monotherapy. Genotyping in 50 children with CH and 52 healthy controls was done using real time PCR. The results showed that there was no statistical difference between the frequencies of genotypes in patients vs. controls. Patients were treated with L-thyroxine and most had normal values for fT3 and fT4. However, high TSH values were found in 21 patients (42%) after treatment. Among patients with high TSH values, AA genotypes were significantly more prevalent (p = 0.044) than TT and AT genotypes. Our results suggest that for the D2 gene Ala92Thr polymorphism, the AA genotype may be detrimental for achieving euthyroidism in patients with CH and levothyroxine monotherapy, therefore polytherapy could be considered as a better approach in these p...
The Journal of Clinical Endocrinology & Metabolism, 2003
Single nucleotide polymorphisms (SNPs) in genes involved in thyroid hormone metabolism may affect thyroid hormone bioactivity. We investigated the occurrence and possible effects of SNPs in the deiodinases (D1-D3), the TSH receptor (TSHR), and the T 3 receptor  (TR) genes. SNPs were identified in public databases or by sequencing of genomic DNA from 15 randomly selected subjects (30 alleles). Genotypes for the identified SNPs were determined in 156 healthy blood donors and related to plasma T 4 , free T 4 , T 3 , rT 3 , and TSH levels. Eight SNPs of interest were identified, four of which had not yet been published. Three are located in the 3-untranslated region: D1a-C/T (allele frequencies, C ؍ 66%, T ؍ 34%), D1b-A/G (A ؍ 89.7%, G ؍ 10.3%), and D3-T/G (T ؍ 85.5%, G ؍ 14.2%). Four are missense SNPs: D2-A/G (Thr92Ala, Thr ؍ 61.2%, Ala ؍ 38.8%), TSHRa-G/C (Asp36His, Asp ؍ 99.4%, His ؍ 0.6%), TSHRb-C/A (Pro52Thr, Pro ؍ 94.2%, Thr ؍ 5.8%), and TSHRc-C/G (Asp727Glu, Asp ؍ 90.7%, Glu ؍ 9.3%). One is a silent SNP: TR-T/C (T ؍ 96.8%, C ؍ 3.2%). D1a-T was associated in a dose-dependent manner with a higher plasma rT 3 [CC, 0.29 ؎ 0.01; CT, 0.32 ؎ 0.01; and TT, 0.34 ؎ 0.02 nmol/liter (mean ؎ SE); P ؍ 0.017], a higher plasma rT 3 /T 4 (P ؍ 0.01), and a lower T 3 /rT 3 (P ؍ 0.003) ratio. The D1b-G allele was associated with lower plasma rT 3 /T 4 (P ؍ 0.024) and with higher T 3 /rT 3 (P ؍ 0.08) ratios. TSHRc-G was associated with a lower plasma TSH (CC, 1.38 ؎ 0.07, vs. GC, 1.06 ؎ 0.14 mU/liter; P ؍ 0.04), and with lower plasma TSH/free T 4 (P ؍ 0.06), TSH/T 3 (P ؍ 0.06), and TSH/T 4 (P ؍ 0.08) ratios. No associations with TSH and iodothyronine levels were found for the other SNPs. We have analyzed eight SNPs in five thyroid hormone pathway genes and found significant associations of three SNPs in two genes (D1, TSHR) with plasma TSH or iodothyronine levels in a normal population. (
Novel insights into thyroid hormones from the study of common genetic variation
Nature Reviews Endocrinology, 2009
| effects of thyroid hormones in individual tissues are determined by many factors beyond their serum levels, including local deiodination and expression and activity of thyroid hormone transporters. These effects are difficult to examine by traditional techniques, but a novel approach that exploits the existence of common genetic variants has yielded new and surprising insights. Convincing evidence indicates a role of type 1 iodothyronine deiodinase (D1) in determining the serum T 4 :T 3 ratio and a role of phosphodiesterase 8B in determining TsH levels. in addition, studies of type 2 iodothyronine deiodinase (D2) variants have shown that thyroid hormones contribute to osteoarthritis and these variants influence intelligence quotient alterations associated with iodine deficiency. Preliminary evidence suggests associations between TsH-receptor variants and fasting glucose level, D1 variants and insulin-like growth factor i production, and D2 variants and hypertension, psychological well-being and response to T 3 or T 4 treatment. intriguingly, most of these associations are independent of serum thyroid hormone levels, which highlights the importance of local regulation of thyroid hormones in tissues. Future research might reveal novel roles for thyroid hormones in obesity, cardiovascular disease, osteoporosis and depression and could have implications for interpretation of thyroid function tests and individualization of thyroid hormone replacement therapy.
Saudi Pharmaceutical Journal, 2019
Background: Deiodinases comprise a group of selenoproteins that regulate the bioavailability of active thyroid hormones (TH) in a time and tissue specific fashion. They increase the hormonal activity by metabolizing their inactive precursors to active forms or terminate their activity by deactivating active hormones. The role of the deiodinase (DIO) gene polymorphisms in thyroid cancer is not fully understood yet. This study evaluated the potential association of the DIO1 and DIO2 genes with differentiated thyroid cancer and differential thyroxine dose requirement in thyroidectomized patients in a Saudi cohort. Methods: We selected four variants (one DIO1 and three DIO2) for the association studies using Taqman assays in 507 DTC patients undergoing treatment with thyroxin against 560 disease-free individual, all of Saudi Arab origin. Results: None of the studied variants was linked to differentiated thyroid cancer. The rs1388378_G > T was initially linked to thyroxine dose requirement (p = 0.035) when all patients were considered together, but this association was lost when the patients were classified into either near suppressed (0.1 TSH < 0.5) or suppressed (TSH < 0.1) TSH group. Discussion: Although the results suggest only a weak relationship with differentiated thyroid cancer, they strongly indicate that the DIO2 polymorphism influences the hormonal dose requirement in patients undergoing treatment with thyroxine. This probably points to a distinction in the way this gene influences disease as compared to therapy thereof.