Dual Effect of a Polymorphism in the Macrophage Migration Inhibitory Factor Gene Is Associated with New-Onset Graves Disease in a Taiwanese Chinese Population

Yu-Huei Liu,Fuu-Jen Tsai,Yi-Ju Chen,Chen-Ming Yang,Ching-Chu Chen,Abhay R Satoskar

doi:10.1371/journal.pone.0092849

Yu-Huei Liu, Fuu-Jen Tsai + Show 4 more

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https://doi.org/10.1371/journal.pone.0092849

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Abstract

Graves disease (GD) is an autoimmune disease. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Two polymorphisms in the promoter region of MIF, rs5844572 and rs755622, are known to affect MIF expression. The purpose of this study was to investigate the relationship between polymorphisms in the MIF gene promoter and the severity of GD. A total of 677 individuals, including 481 GD patients and 196 ethnically matched healthy controls, were genotyped to identify differences in the distribution of the MIF polymorphisms rs5844572 and rs755622. Although there were no significant differences in the allele or genotype distributions among patients with different grades of goiter in GD and healthy controls, the distribution of the C allele, especially C/C genotype, of the rs755622 single nucleotide polymorphism (SNP) in MIF, may be as a risk factor for goiter initiation whereas a protector against development of severe goiter in patients with untreated GD (p<0.05). A goiter-developmental model incorporating genetic (MIF SNP rs755622) and environmental risk factors (gender, radioiodine treatment, thyroid gland surgery and vitiligo) significantly increased the prediction accuracy. Further studies are required to address the role of MIF polymorphisms, as well as their association with other candidate genes, in GD.

Highlights

Graves disease (GD) is an autoimmune thyroid disease that occurs in approximately 5–12 per 1000 people in Western populations and in 3–11 per 1000 people in Chinese populations [1,2]
Robust evidence from genome-wide association analyses has helped identify some of the GD-associated polymorphisms, such as those in the thyroid-stimulating hormone receptor (TSHR), thyroglobulin, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), and Fc receptor-like 3 (FCRL3) genes; the results of these studies reiterate the complexity of the disease and the need for detection of additional genetic determinants of GD [4,5,6,7,8,9,10,11]
The C allele of the rs755622 single nucleotide polymorphism (SNP) in migration inhibitory factor (MIF) is associated with goiter severity in patients with untreated GD. Because medical therapies such as radioiodine treatment, thyroid gland surgery, and other drugs may reduce the severity of GD-associated phenotypes subsequently altering the polymorphism-related phenotype, we examined the association of the polymorphisms with the severity of goiter using a stratified method of analysis, in which the patients were stratified based on whether the GD was euthyroid, untreated or treated

Summary

Introduction

Graves disease (GD) is an autoimmune thyroid disease that occurs in approximately 5–12 per 1000 people in Western populations and in 3–11 per 1000 people in Chinese populations [1,2]. Robust evidence from genome-wide association analyses has helped identify some of the GD-associated polymorphisms, such as those in the thyroid-stimulating hormone receptor (TSHR), thyroglobulin, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), and Fc receptor-like 3 (FCRL3) genes; the results of these studies reiterate the complexity of the disease and the need for detection of additional genetic determinants of GD [4,5,6,7,8,9,10,11]. Overexpression and secretion of MIF help restore macrophage cytokine production and T cell activity in response to the immunosuppressive effects of glucocorticoids [15]. Some studies suggest that MIF might be associated with alterations in thyroid hormone secretion in certain diseases [18,19,20].

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