Dual effect of a polymorphism in the macrophage migration inhibitory factor gene is associated with new-onset Graves disease in a Taiwanese Chinese population

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_{Department of Medical Research, China Medical University Hospital;}

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_{Graduate Institute of Integrated Medicine, China Medical}

University;

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_{Department of Pediatrics, China Medical University Hospital;}

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_{School of Chinese Medicine, China Medical University;}

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_{School of Post}

_{School of Post----Baccalaureate Chinese Medicine, China Medical University;}

_{School of Post}

_{Baccalaureate Chinese Medicine, China Medical University;}

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_{Institute of Biochemical Sciences, National Taiwan}

University

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Yi----Ju

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Ju Chen

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_{, Chen----Ming Yang}

_{, Chen}

_{Ming Yang}

1, 61, 61, 61, 6

_{, , , , Fuu}

_{Fuu----Jen Tsai}

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_{Jen Tsai}

1, 3, 4, 5*1, 3, 4, 5*1, 3, 4, 5*1, 3, 4, 5*

_{, Yu----Huei}

_{, Yu}

_Huei

_{Huei Liu}

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_Liu

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Abstract

Backgrounds:

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.

Materials and Methods:

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.

Results:

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).

Conclusion:

Agoiter-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.

Summary

In summary, our ﬁndings provide new information pertaining to the role of MIF gene polymorphisms and show that the rs755622 SNP is associated with the severity of goiter in patients with untreated GD in a Taiwanese Chinese population. These data suggest the need for additional studies in larger cohorts to address the role of MIF polymorphisms in the pathogenesis of GD as well as their relationship with other candidate genes with known/putative functions in GD.

Results

Allele and genotype distribution of MIF in GD patients and healthy controls

The demographic information and clinical characteristics of the 481 GD patients enrolled in this study are summarized in Table 1. The frequency of the polymorphisms examined was similar to those of the Chinese and Japanese (CHB and JPT) components of HapMap. No deviation from Hardy-Weinberg equilibrium was observed for allele frequencies of the rs5844572 and rs755622 polymorphisms in the MIF gene (P >0.05).

The C allele of the rs755622 SNP in MIF is associated with goiter severity in patients with

untreated GD

We next 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. It is notable that both the allele and genotype distribution of the rs755622 SNP in MIF showed associations with the severity of goiter in patients with untreated GD (GD patients vs healthy controls, P = 0.006 for allele distribution and P = 0.009 for genotype distribution; among GD patients with goiter of different grades, P = 0.002 for allele distribution and P = 0.001 for genotype distribution; Table 3).

A-priori analysis revealed that the minimum total sample size (two-tailed hypothesis) is 46 when consider the difference of untreated GD patients with grade 0 goiter and other groups. Therefore the comparison between GD patients with grade 0 goiter and healthy controls, as well as GD patients with grade 0 goiter and those with grade 2 goiter, were further analyzed. Logistic regression analyses revealed that in the untreated group, GD patients with the C allele may be risk for initial goiter development (odds ratio (OR): 5.821, 95% confidence interval (CI): 1.978-18.843 for GD patients with grade 0 goiter as compared to healthy individuals), but may be protected from severe goiter development (OR: 0.133, 95%CI: 0.040-0.438 for GD patients with goiter of grade 2, as compared to those with grade 0 goiter; Table 4). In addition, the C/C genotype may be risk for initial goiter development (OR: 32.000, 95%CI: 2.615-391.587 for GD patients with grade 0 goiter as compared to healthy individuals), but protective against development of severe goiter (OR: 0.016, 95%CI: 0.001-0.226 for GD patients with goiter of grades 1b, 2 and 3, respectively, as compared to those with grade 0 goiter; Table 4). These results suggest that the C allele of the rs755622 SNP in MIF, especially the C/C genotype, may play a role as risk factor for goiter initiation, and may play a protective role against development of severe goiter in patients with untreated GD.

The C allele of the rs755622 SNP in MIF and other clinical features of

Graves disease

A comparison of clinical features [gender, age, frequency of radioiodine treatment, thyroid gland surgery, ophthalmopathy, nodular hyperplasia, myxedema, vitiligo, cigarette smoking habit, as well as thyroid functions including initial FT4, TSH and anti-thyroid hormone receptor antibody (TRAb) levels amongrs755622 genotypes (G/G and G/C+C/C)] was shown. Results suggest that in the untreated group, the rs755622 SNP in MIF is also associated with age, thyroid gland surgery and vitiligo (Table 5). However, the rs755622 SNP in MIF was shown no association toward any thyroid function in the untreated group (Table 5).

The distribution of the MIF polymorphisms among patients with different severities of goiter (grades 0, 1A, 1B, 2, and 3) as well as in healthy controls were analyzed. A-priori analysis revealed that the minimum total sample size (two-tailed hypothesis) is 98 when consider the difference of GD patients with grade 0 goiter and other groups. The allele and genotype distributions of the rs5844572 and rs755622 polymorphisms in MIF were not significantly different among the patient and control groups (P >0.05; Table 2).

Multifactor dimensionality reduction analysis

To extend the previous findings, the interaction between rs755622 SNP in MIF and other non-genetic factors on the severity of goiter (0 vs 1a/1b/2/3) in untreated GD patients was determined by using the MDR analysis. The results suggested that as compared to the one-factor model, rs755622 genotype of MIF (G/G, G/C + C/C) (testing balance accuracy: 77.08%, OR (95%CI):12.143 (1.387-106.298), P = 0.0047), the 5-factor model consisted of the aforementioned genotype and the additional factors including gender, radioiodine treatment, thyroid gland surgery, and vitiligo showed to increase the prediction accuracy (testing balance accuracy: 86.72%, OR (95%CI): ∞, P <1.000× 10-4_{). The interaction dendrogram was shown in Figure 1.}