Genes that characterize T3-predominant Graves' thyroid tissues

Abstract

Objective: 3,5,3 0 -Triiodothyronine (T 3 )-predominant Graves' disease is characterized by the increasing volume of thyroid goiter resulting in poor prognosis. Although type 1 and type 2 iodothyronine deiodinases (DIO1 and DIO2 respectively) are known to be overexpressed in the thyroid tissues of T 3 -predominant Graves' disease, the pathogenesis of this disease is still unclear. The aim of our study is to identify genes that characterize T 3 -predominant Graves' disease tissue in order to clarify the molecular mechanism of this disease. Design and methods: mRNAs from two thyroid tissues of both typical T 3 -predominant and common-type Graves' disease were analyzed with DNA microarrays with probes for 28 869 genes. Genes identified to be differentially expressed between the two groups were further analyzed in the second and third screenings using 70 Graves' thyroid tissues by real-time quantitative RT-PCR. Results: Twenty-three candidate genes were selected as being differentially expressed in the first screening with microarrays. Among these, seven genes, leucine-rich repeat neuronal 1 (LRRN1), bone morphogenetic protein 8a (BMP8A), N-cadherin (CDH2), phosphodiesterase 1A (PDE1A), creatine kinase mitochondrial 2 (CKMT2), integrin beta-3 (ITGB3), and protein tyrosine phosphatase nonreceptor type 4 (PTPN4), were confirmed to be differentially expressed in DIO1 or DIO2 over-and underexpressing Graves' tissues. Conclusions: These genes are related to the characteristics of T 3 -predominant Graves' disease, such as high titer level of serum anti-TSH receptor antibody, high free T 3 to free thyroxine ratio, and a large goiter size. They might play a role in the pathogenesis of T 3 -predominant Graves' disease.

MANAGEMENT OF ENDOCRINE DISEASE: Arguments for the prolonged use of antithyroid drugs in children with Graves’ disease

“…These patients therefore have a high fT3:fT4 ratio, making it necessary to determine serum free T3 concentrations in patients with long-term undetectable TSH levels, to identify cases with this presentation. These patients have larger thyroid glands and high serum titers of TRAb (21,22,23). They are more likely to be younger and require doses of ATD twice as high as those used in patients with classic GD, over long periods of time, although it remains unclear why the maintenance of high doses is required to overcome the resistance to ATD (21).…”

Fetal cell carcinogenesis of the thyroid: A modified theory based on recent evidence [My Opinion]

“…Some recent studies reported an interesting similarity in gene expression between tissues from T 3 predominant Graves' disease and hyperfunctioning adenomas. They overexpress not only iodothyronine deiodinases but also N-cadherin (CDH2) [54,55]. If T 3 predominant Graves' disease is caused by an increased number of fetal thyroid cells, probably prothyrocytes, some clinical features of T 3 -predominant Graves' disease, such as its high prevalence in the young and tendency to form a large goiter, are easily explained.…”

Study of Deiodinase Type 2 Polymorphisms in Graves’ Disease and Ophthalmopathy in a Swedish Population

“…TRAb increases intrathyroidal DIO2 expression and activity, and increased intrathyroidal DIO2 activity may contribute significantly to the relative increase in thyroidal T3 production in GD patients [4]. Two Japanese studies aiming at characterizing the T3-predominant type of GD observed overexpression and increased thyroidal DIO2 activity as well as a high serum fT3/fT4 ratio in patients with T3-predominant GD [29,30]. Thus, DIO2 gene polymorphisms could further modulate these responses.…”