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Open Access Highly Accessed Research article

Thymic stromal lymphopoietin gene promoter polymorphisms and expression levels in Graves’ disease and Graves’ ophthalmopathy

Kun-Hsi Tsai1, Fuu-Jen Tsai23, Hui-Ju Lin4, Hung-Jung Lin1, Yu-Huei Liu25, Wen-Ling Liao2 and Lei Wan267*

Author Affiliations

1 Department of Emergency Medicine, Chi Mei Hospital, Liouying, Tainan, Taiwan

2 Genetic Center, China Medical University Hospital, 404, Taichung, Taiwan

3 School of Post Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan

4 Department of ophthalmology, China Medical University Hospital, Taichung, Taiwan

5 Graduate Institute of Integrated medicine, China Medical University, Taichung, Taiwan

6 School of Chinese Medicine, China Medical University, Taichung, Taiwan

7 Department of Biotechnology, Asia University, Taichung, Taiwan

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BMC Medical Genetics 2012, 13:116  doi:10.1186/1471-2350-13-116

Published: 30 November 2012

Abstract

Background

Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation.

Methods

In this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined.

Results

Haplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10−14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients.

Conclusions

These results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.

Keywords:
Graves’ disease; Graves’ ophthalmopathy; Thymic stromal lymphopoietin; Th17